Thrombin or factor Xa inhibitors

ABSTRACT

This invention relates generally to inhibitors of trypsin-like serine protease enzymes, especially factor Xa or thrombin, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.

This application claims the benefit of U.S. Provisional application No.60/113,627, filed Dec. 23, 1998.

FIELD OF THE INVENTION

This invention relates generally to inhibitors of trypsin-like serineprotease enzymes, especially factor Xa or thrombin, pharmaceuticalcompositions containing the same, and methods of using the same asanticoagulant agents for treatment and prevention of thromboembolicdisorders.

BACKGROUND OF THE INVENTION

Activated factor Xa, whose major practical role is the generation ofthrombin by the limited proteolysis of prothrombin, holds a centralposition that links the intrinsic and extrinsic activation mechanisms inthe final common pathway of blood coagulation. The generation ofthrombin, the final serine protease in the pathway to generate a fibrinclot, from its precursor is amplified by formation of prothrombinasecomplex (factor Xa, factor V, Ca²⁺ and phospholipid). Since it iscalculated that one molecule of factor Xa can generate 138 molecules ofthrombin (Elodi, S., Varadi, K.: Optimization of conditions for thecatalytic effect of the factor IXa-factor VIII Complex: Probable role ofthe complex in the amplification of blood coagulation. Thromb. Res.1979, 15, 617-629), inhibition of factor Xa may be more efficient thaninactivation of thrombin in interrupting the blood coagulation system.

Therefore, efficacious and specific inhibitors of factor Xa, thrombin,or both are needed as potentially valuable therapeutic agents for thetreatment of thromboembolic disorders. It is thus desirable to discovernew factor Xa, thrombin, or both inhibitors.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novelnitrogen containing aromatic heterocycles, with ortho-substituted P1groups, which are useful as factor Xa inhibitors or pharmaceuticallyacceptable salts or prodrugs thereof.

It is another object of the present invention to provide pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

It is another object of the present invention to provide a method fortreating thromboembolic disorders comprising administering to a host inneed of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention or a pharmaceuticallyacceptable salt or prodrug form thereof.

It is another object of the present invention to provide novel compoundsfor use in therapy.

It is another object of the present invention to provide the use ofnovel compounds for the manufacture of a medicament for the treatment ofthrombosis or a disease mediated by factor Xa.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[1] Thus, in an embodiment, the present invention provides a novelcompound selected from the group:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

G is selected from the group:

L_(n) is a linker which is absent or is selected from O, S, CH₂,

*CH₂NHC(O), *CH(R^(a))NHC(O), *CH₂NHC(O)CH₂, and

*CH(R^(a))NHC(O)CH₂, provided that L_(n) and M do not form an O—N or S—Nbond and the * indicates where L_(n) is bonded to G;

M¹ is absent or is CHR;

M² is N or CR^(f);

M³ is N or CR^(d);

provided that only one of M² and M³ is N;

R^(a) is selected from C(O)C(O)OR³, C(O)C(O)NR²R^(2a), and C(O)—A;

R^(b) is selected from H, R, phenyl, C₁₋₁₀ alkyl, and C₂₋₅ alkenyl;

R^(c) is selected from H and C₁₋₆ alkyl;

alternatively, R^(b) and R^(c) together are —(CH₂)₄—;

R^(d) is selected from H, F, and Cl;

R^(e) is selected from H, N(CH₃)(CH₂CO₂H) and S-(5-6 membered aromaticheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S substituted with 0-2 R⁴);

alternatively, R^(d) and R^(e) combine to form—NR³—C(O)—C(R^(1b)R³)—NR³— or —N═CR²—NR³—;

R^(f) is selected from H, F, and Cl;

alternatively, R^(e) and R^(f) combine to form—NR³—C(R^(1b)R³)—C(O)—NR³— or —NR³—CR²═N—;

R^(g) is selected from H, CH₂OR³, CH₂C(O)OR³, C₁₋₄ alkyl, C(O)NH₂, andNH₂;

R^(h) is selected from H, CH₂-phenyl, CH₂CH₂-phenyl, and CH═CH-phenyl;

R^(i) is selected from SO₂CH₂C(O)OR³, C(O)CH₂C(O)OR³, and C(O)OR³;

R is selected from H, Cl, F, Br, I, (CH₂)_(t)OR³, C₁₋₄ alkyl, benzyl,OCF₃, CF₃, C(O)NR⁷R⁸, and (CR⁸R⁹)_(t)NR⁷R⁸;

Z is selected from a (CR⁸R⁹)₁₋₄, (CR⁸R⁹)_(r)O(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)NR³(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)C(O)(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)C(O)O(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)OC(O)(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)C(O)NR³(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)NR³C(O)(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)OC(O)O(CR⁸R⁹)_(r), (CH₂)_(r)OC(O)NR₃(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)NR³C(O)O(CR⁸R⁹)_(r), (CH₂)_(r)NR³C(O)NR³(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)S(O)_(p)(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)S(O)₂(CH═CH),(CCR⁸R⁹)_(r)SO₂NR³(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)NR³SO₂(CR⁸R⁹)_(r), and(CR⁸R⁹)_(r)NR³SO₂NR³(CR⁸R⁹)_(r), provided that Z does not form a N—N,N—O, N—S, NCH₂N, NCH₂O, or NCH₂S bond with the groups to which Z isattached;

R^(1a) is absent or selected from —(CH₂)_(r)—R^(1′), —CH═CH—R^(1′),NHCH₂R^(1″), OCH₂R^(1″), SCH₂R^(1″), NH(CH₂)₂(CH₂)_(t)R^(1′),O(CH₂)₂(CH₂)_(t)R^(1′), and S(CH₂)₂(CH₂)_(t)R^(1′);

R^(1′) is selected from H, C₁₋₃ alkyl, F, Cl, Br, I, —CN, —CHO,(CF₂)_(r)CF₃, (CH₂)_(r)OR², NR²R^(2a), C(O)R^(2c), OC(O)R²,(CF₂)_(r)CO₂R^(2c), S(O)_(p)(CH₂)_(r)R^(2b), NR²(CH₂)_(r)OR²,C(═NR^(2c))NR²R^(2a), NR²C(O)R^(2b), NR²C(O)NHR^(2b), NR²C(O)₂R^(2a),OC(O)NR^(2a)R^(2b), C(O)NR²R^(2a), C(O)NR²(CH₂)_(r)OR², SO₂NR²R^(2a),NR²SO₂R^(2b), C₃₋₆ carbocyclic residue substituted with 0-2 R⁴, and 5-10membered heterocyclic system containing from 1-4 heteroatoms selectedfrom the group consisting of N, O, and S substituted with 0-2 R⁴;

R^(1″) is selected from H, CH(CH₂OR²)₂, C(O)R^(2c), C(O)NR²R^(2a),S(O)R^(2b), S(O)₂R^(2b), and SO₂NR²R^(2a);

R^(1b) is selected from H, C₁₋₆ alkyl, and C₁₋₆ alkyl substituted withA;

R², at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl,C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 memberedheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S substituted with 0-2 R^(4b);

R^(2a), at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl,C₃₋₆ cycloalkylmethyl substituted with 0-2 R^(4b), C₃₋₆ carbocyclicresidue substituted with 0-2 R^(4b), and 5-6 membered heterocyclicsystem containing from 1-4 heteroatoms selected from the groupconsisting of N, O, and S substituted with 0-2 R^(4b);

R^(2b), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy, C₁₋₆alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and5-6 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R^(4b);

R^(2c), at each occurrence, is selected from CF₃, OH, C₁₋₄ alkoxy, C₁₋₆alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and5-6 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R^(4b);

alternatively, R² and R^(2a), together with the atom to which they areattached, combine to form a 5 or 6 membered saturated, partiallysaturated or unsaturated ring substituted with 0-2 R^(4b) and containingfrom 0-1 additional heteroatoms selected from the group consisting of N,O, and S;

R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

R^(3a), at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

R^(3b), at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

R^(3c), at each occurrence, is selected from C₁₋₄ alkyl, and phenyl;

A is selected from:

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁴, and

5-10 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R⁴;

A¹ is H or A;

alternatively, A and A¹ and the carbon to which they are attachedcombine to form fluorene;

A² is selected from H, A, and CHA³A⁴;

A³ is selected from H, A, C₁₋₄ alkyl, and —(CH₂)_(r)NR²R^(2a);

A⁴ is H or A;

B is selected from: H, Y, and X—Y

X is selected from C₁₋₄ alkylene, —CR²(CR²R^(2b))(CH₂)_(t)—, —C(O)—,—CR²(NR^(1″)R²)—, —CR²(OR²)—, —CR²(SR²)—, —C(O)CR²R^(2a)—,—CR²R^(2a)C(O), —OS(O)₂—, —S(O)_(p)—, —S(O)_(p)CR²R^(2a)—,—CR²R^(2a)S(O)_(p)—, —S(O)₂NR²—, —NR₂S(O)₂—, —NR²S(O)₂CR²R^(2a)—,—CR²R^(2a)S(O)₂NR²—, —NR²S(O)₂NR²—, —C(O)NR²—, —NR²C(O)—,—C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—, —CR²R^(2a)C(O)NR²—,—CR²R^(2a)NR²C(O)—, —NR²C(O)O—, —OC(O)NR²—, —NR²C(O)NR²—, —NR²—,—NR²CR²R^(2a), —CR²R^(2a)NR²—, O, —CR²R^(2a)O—, and —OCR²R^(2a)—;

Y is selected from:

(CH₂)_(r)NR²R^(2a), provided that X—Y do not form a N—N, O—N, or S—Nbond,

C₃₋₁₀ carbocyclic residue substituted with 0-2 R^(4a), and

5-10 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R^(4a);

alternatively, Z—A—B combine to form S—C₁₋₆ alkyl;

R⁴, at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², F, Cl, Br,I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),NR²C(O)R^(2b), C(O)NR²R^(2a), NR²C(O)NR²R^(2a), C(═NR²)NR²R^(2a),C(═NS(O)₂R⁵)NR²R^(2a), NHC(═NR²)NR²R^(2a), C(O)NHC(═NR²)NR²R^(2a),SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵,(CF₂)_(r)CF₃, NHCH₂R^(1″), OCH₂R^(1″), SCH₂R^(1″),N(CH₂)₂(CH₂)_(t)R^(1′), O(CH₂)₂(CH₂)_(t)R^(1′), andS(CH₂)₂(CH₂)_(t)R^(1′);

alternatively, one R⁴ is a 5-6 membered aromatic heterocycle containingfrom 1-4 heteroatoms selected from the group consisting of N, O, and S;

R^(4a), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR²,(CH₂)_(r)—F, (CH₂)_(r)—Br, (CH₂)_(r)—Cl, Cl, Br, F, I, C₁₋₄ alkyl, —CN,NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b),C(O)NR²R^(2a), C(O)NH(CH₂)₂NR²R^(2a), NR²C(O)NR²R^(2a), C(═NR²)R^(3c),C(═NR²)NR²R^(2a), NHC(═NR₂)NR²R^(2a), SO₂NR²R^(2a), NR²SO²NR²R^(2a),NR²SO₂—C₁₋₄ alkyl, C(O)NHSO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, and(CF₂)_(r)CF₃;

alternatively, one R^(4a) is a 5-6 membered aromatic heterocyclecontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-1 R⁵;

R^(4b), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR³, F, Cl,Br, I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³,(CH₂)_(r)C(O)OR^(3c), NR³C(O)R^(3a), C(O)NR³R^(3a), NR³C(O)NR³R^(3a),C(═NR³)NR³R^(3a), NR³C(═NR³)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂NR³R^(3a),NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃, NR³SO₂-phenyl S(O)_(p)CF₃, S(O)_(p)—C₁₋₄alkyl, S(O)_(p)-phenyl, and (CF₂)_(r)CF₃;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenylsubstituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶;

R⁶, at each occurrence, is selected from H, OH, (CH₂)_(r)OR², halo, C₁₋₄alkyl, CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b),NR²C(O)NR²R^(2a), C(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂NR²R^(2a),and NR²SO₂C₁₋₄ alkyl;

R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, (CH₂)_(n)-phenyl, C₆₋₁₀aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenylC₁₋₄ alkoxycarbonyl;

R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and(CH₂)_(n)-phenyl;

alternatively, R⁷ and R⁸ combine to form a 5 or 6 membered saturated,ring which contains from 0-1 additional heteroatoms selected from thegroup consisting of N, O, and S;

R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl and(CH₂)_(n)-phenyl;

R¹⁰ is selected from H, phenyl substituted with 0-2 R^(4a), and naphthylsubstituted with 0-2 R^(4a);

n, at each occurrence, is selected from 0, 1, 2, and 3;

m, at each occurrence, is selected from 0, 1, and 2;

p, at each occurrence, is selected from 0, 1, and 2;

r, at each occurrence, is selected from 0, 1, 2, and 3;

s, at each occurrence, is selected from 0, 1, and 2; and,

t, at each occurrence, is selected from 0, 1, 2, and 3.

[2] Thus, in another embodiment, the present invention provides a novelcompound selected from the group:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

G is selected from the group:

L_(n) is a linker which is absent or is selected from O, S, CH₂,

*CH₂NHC(O), *CH(R^(a))NHC(O), *CH₂NHC(O)CH₂, and

*CH(R^(a))NHC(O)CH₂, provided that L_(n) and M do not form an O—N or S—Nbond and the * indicates where L_(n) is bonded to G;

M¹ is absent or is CHR;

M² is N or CR^(f);

M³ is N or CR^(d) ;

provided that only one of M² and M³ is N;

R^(a) is selected from C(O)C(O)OR³, C(O)C(O)NR²R^(2a), and C(O)—A;

R^(b) is selected from H, R, phenyl, C₁₋₁₀ alkyl, and C₂₋₅ alkenyl;

R^(c) is selected from H and C₁₋₆ alkyl;

alternatively, R^(b) and R^(c) together are —(CH₂)₄—;

R^(d) is selected from H, F, and Cl;

R^(e) is selected from H, N(CH₃)(CH₂CO₂H) and S-(5-6 membered aromaticheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S substituted with 0-2 R⁴);

alternatively, R^(d) and R^(e) combine to form—NR³—C(O)—C(R^(1b)R³)—NR³— or —N═CR²—NR³—;

R^(f) is selected from H, F, and Cl;

alternatively, R^(e) and R^(f) combine to form—NR³—C(R^(1b)R³)—C(O)—NR³— or —NR³—CR²═N—;

R^(g) is selected from H, CH₂OR³, CH₂C(O)OR³, C₁₋₄ alkyl, C(O)NH₂, andNH₂;

R^(h) is selected from H, CH₂-phenyl, CH₂CH₂-phenyl, and CH═CH-phenyl;

R^(i) is selected from SO₂CH₂C(O)OR³, C(O)CH₂C(O)OR³, and C(O)OR³;

R is selected from H, Cl, F, Br, I, (CH₂)_(t)OR³, C₁₋₄ alkyl, benzyl,OCF₃, CF₃, C(O)NR⁷R⁸, and (CR⁸R⁹)_(t)NR⁷R⁸;

Z is selected from a (CR⁸R⁹)₁₋₄, (CR⁸R⁹)_(r)O(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)NR³(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)C(O)(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)C(C)O(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)OC(O)(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)C(O)NR³(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)NR³C(O)(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)OC(C)O(CR⁸R⁹)_(r), (CH₂)_(r)OC(O)NR³(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)NR³C(O)O(CR⁸R⁹)_(r), (CH₂)_(r)NR³C(O)NR³(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)S(O)_(p)(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)S(O)₂(CH═CH),(CCR⁸R⁹)_(r)SO₂NR³(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)NR³SO₂(CR⁸R⁹)_(r), and(CR⁸R⁹)_(r)NR³SO₂NR³(CR⁸R⁹)_(r), provided that Z does not form a N—N,N—O, N—S, NCH₂N, NCH₂O, or NCH₂S bond with the groups to which Z isattached;

R^(1a) is absent or selected from —(CH₂)_(r)—R^(1′), —CH═CH—R^(1′),NHCH₂R^(1″), OCH₂R^(1″), SCH₂R^(1″), NH(CH₂)₂(CH₂)_(t)R^(1′),O(CH₂)₂(CH₂)_(t)R^(1′), and S(CH₂)₂(CH₂)_(t)R^(1′);

R^(1′) is selected from H, C₁₋₃ alkyl, F, Cl, Br, I, —CN, —CHO,(CF₂)_(r)CF₃, (CH₂)_(r)OR², NR²R^(2a), C(O)R^(2c), OC(O)R²,(CF₂)_(r)CO₂R^(2c), S(O)_(p)(CH₂)_(r)R^(2b), NR²(CH₂)_(r)OR²,C(═NR^(2c))NR²R^(2a), NR²C(O)R^(2b), NR²C(O)NHR^(2b), NR²C(O)₂R^(2a),OC(O)NR^(2a)R^(2b), C(O)NR²R^(2a), C(O)NR²(CH₂)_(r)OR², SO₂NR²R^(2a),NR²SO₂R^(2b), C₃₋₆ carbocyclic residue substituted with 0-2 R⁴, and 5-10membered heterocyclic system containing from 1-4 heteroatoms selectedfrom the group consisting of N, O, and S substituted with 0-2 R⁴;

R^(1″) is selected from H, CH(CH₂OR²)₂, C(O)R^(2c), C(O)NR²R^(2a),S(O)R^(2b), S(O)₂R^(2b), and SO₂NR²R^(2a);

R^(1b) is selected from H, C₁₋₆ alkyl, and C₁₋₆ alkyl substituted withA;

R², at each occurrence, is selected from H, CF₃, C₁₆ alkyl, benzyl, C₃₋₆carbocyclic residue substituted with 0-2 R^(4b), and 5-6 memberedheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S substituted with 0-2 R^(4b);

R^(2a), at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl,C₃₋₆ cycloalkylmethyl substituted with 0-2 R^(4b), C₃₋₆ carbocyclicresidue substituted with 0-2 R^(4b), and 5-6 membered heterocyclicsystem containing from 1-4 heteroatoms selected from the groupconsisting of N, O, and S substituted with 0-2 R^(4b);

R^(2b), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy, C₁₋₆alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and5-6 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R^(4b);

R^(2c), at each occurrence, is selected from CF₃, OH, C₁₋₄ alkoxy, C₁₋₆alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and5-6 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R^(4b);

alternatively, R² and R^(2a), together with the atom to which they areattached, combine to form a 5 or 6 membered saturated, partiallysaturated or unsaturated ring substituted with 0-2 R^(4b) and containingfrom 0-1 additional heteroatoms selected from the group consisting of N,O, and S;

R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

R^(3a), at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

R^(3b), at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

R^(3c), at each occurrence, is selected from C₁₋₄ alkyl, and phenyl;

A is selected from:

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁴, and

5-10 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R⁴;

A¹ is H or A;

alternatively, A and A¹ and the carbon to which they are attachedcombine to form fluorene;

A² is selected from H, A, and CHA³A⁴;

A³ is selected from H. A, C₁₋₄ alkyl, and —(CH₂)_(r)NR²R^(2a);

A⁴ is H or A;

B is selected from: H, Y, and X—Y

X is selected from C₁₋₄ alkylene, —CR²(CR²R^(2b))(CH₂)_(t)—, —C(O)—,—CR²(NR^(1″)R²)—, —CR²(OR²)—, —CR²(SR²)—, —C(O)CR²R^(2a),—CR²R^(2a)C(O), —OS(O)₂—, —S(O)_(p)—, —S(O)_(p)CR²R^(2a)—,—CR²R^(2a)S(O)_(p)—, —S(O)₂NR²—, —NR²S(O)₂—, —NR²S(O)₂CR²R^(2a)—,—CR²R^(2a)S(O)₂NR²—, —NR²S(O)₂NR²—, —C(O)NR²—, —NR²C(O)—,—C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—, —CR²R^(2a)C(O)NR²—,—CR²R^(2a)NR²C(O)—, —NR²C(O)O—, —OC(O)NR²—, —NR²C(O)NR²—, —NR²—,NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, —CR²R^(2a)O—, and —OCR²R^(2a)—;

Y is selected from:

(CH₂)_(r)NR²R^(2a), provided that X—Y do not form a N—N, O—N, or S—Nbond,

C₃₋₁₀ carbocyclic residue substituted with 0-2 R^(4a), and

5-10 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R^(4a);

alternatively, Z—A—B combine to form S—C₁₋₆ alkyl;

R⁴, at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², F, Cl, Br,I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),NR²C(O)R^(2b), C(O)NR²R^(2a), NR²C(O)NR²R^(2a), C(═NR²)NR²R^(2a),C(═NS(O)₂R⁵)NR²R^(2a), NHC(═NR²)NR²R^(2a), C(O)NHC(═NR²)NR²R^(2a),SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵,(CF₂)_(r)CF₃, NHCH₂R^(1″), OCH₂R^(1″), SCH₂R^(1″),N(CH₂)₂(CH₂)_(t)R^(1′), O(CH₂)₂(CH₂)_(t)R^(1′), andS(CH₂)₂(CH₂)_(t)R^(1′);

alternatively, one R⁴ is a 5-6 membered aromatic heterocycle containingfrom 1-4 heteroatoms selected from the group consisting of N, O, and S;

R^(4a), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR²,(CH₂)_(r)—F, (CH₂)_(r)—Br, (CH₂)_(r)—Cl, Cl, Br, F, I, C₁₋₄ alkyl, —CN,NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b),C(O)NR²R^(2a), C(O)NH(CH₂)₂NR²R^(2a), NR²C(O)NR²R^(2a), C(═NR²)R^(3c),C(═NR²)NR²R^(2a), NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a),NR²SO₂—C₁₋₄ alkyl, C(O)NHSO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, and(CF₂)_(r)CF₃;

alternatively, one R^(4a) is a 5-6 membered aromatic heterocyclecontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-1 RS;

R^(4b), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR³, F, Cl,Br, I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³,(CH₂)_(r)C(O)OR^(3c), NR³C(O)R^(3a), C(O)NR³R^(3a), NR³C(O)NR³R^(3a),C(═NR³)NR³R^(3a), NR³C(═NR³)NR³R^(3a), NR^(3a), SO₂NR³R^(3a),NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃, NR³SO₂-phenyl S(O)_(p)CF₃, S(O)_(p)—C₁₋₄alkyl, S(O)_(p)-phenyl, and (CF₂)_(r)CF₃;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenylsubstituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶;

R⁶, at each occurrence, is selected from H, OH, (CH₂)_(r)OR², halo, C₁₋₄alkyl, CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b),NR²C(O)NR²R^(2a), C(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂NR²R^(2a),and NR²SO₂C₁₋₄ alkyl;

R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, (CH₂)_(n)-phenyl, C₆₋₁₀aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenylC₁₋₄ alkoxycarbonyl;

R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and(CH₂)_(n)-phenyl;

alternatively, R⁷ and R⁸ combine to form a 5 or 6 membered saturated,ring which contains from 0-1 additional heteroatoms selected from thegroup consisting of N, O, and S;

R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl and(CH₂)_(n)-phenyl;

R¹⁰ is selected from H, phenyl substituted with 0-2 R^(4a), and naphthylsubstituted with 0-2 R^(4a);

n, at each occurrence, is selected from 0, 1, 2, and 3;

m, at each occurrence, is selected from 0, 1, and 2;

p, at each occurrence, is selected from 0, 1, and 2;

r, at each occurrence, is selected from 0, 1, 2, and 3;

s, at each occurrence, is selected from 0, 1, and 2; and,

t, at each occurrence, is selected from 0, 1, 2, and 3.

[3] Thus, in another embodiment, the present invention provides a novelcompound selected from the group:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

G is selected from the group:

L_(n) is a linker which is absent or is selected from O, S, CH₂,

*CH₂NHC(O), *CH(R^(a))NHC(O), *CH₂NHC(O)CH₂, and

*CH(R^(a))NHC(O)CH₂, provided that L_(n) and M do not form an O—N or S—Nbond and the * indicates where L_(n) is bonded to G;

M¹ is absent or is CHR;

M² is N or CR^(f);

M³ is N or CR^(d) ;

provided that only one of M² and M³ is N;

R^(a) is selected from C(O)C(O)OR³, C(O)C(O)NR²R^(2a), and C(O)—A;

R^(b) is selected from H, R, phenyl, C₁₋₁₀ alkyl, and C₂₋₅ alkenyl;

R^(c) is selected from H and C₁₋₆ alkyl;

alternatively, R^(b) and R^(c) together are —(CH₂)₄—;

R^(d) is selected from H, F, and Cl;

R^(e) is selected from H, N(CH₃)(CH₂CO₂H) and S-(5-6 membered aromaticheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S substituted with 0-2 R⁴);

alternatively, R^(d) and R^(e) combine to form—NR³—C(O)—C(R^(1b)R³)—NR³— or —N═CR²—NR³—;

R^(f) is selected from H, F, and Cl;

alternatively, R^(e) and R^(f) combine to form—NR³—C(R^(1b)R³)—C(O)—NR³— or —NR³—CR²═N—;

R^(g) is selected from H, CH₂OR³, CH₂C(O)OR³, C₁₋₄ alkyl, C(O)NH₂, andNH₂;

R^(h) is selected from H, CH₂-phenyl, CH₂CH₂-phenyl, and CH═CH-phenyl;

R^(i) is selected from SO₂CH₂C(O)OR³, C(O)CH₂C(O)OR³, and C(O)OR³;

R is selected from H, Cl, F, Br, I, (CH₂)_(t)OR³, C₁₋₄ alkyl, benzyl,OCF₃, CF₃, C(O)NR⁷R⁸, and (CR⁸R⁹)_(t)NR⁷R⁸;

Z is selected from a (CR⁸R⁹)₁₋₄, (CR⁸R⁹)_(r)O(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)NR³(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)C(O)(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)C(O)O(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)OC(O)(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)C(O)NR³(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)NR³C(O)(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)OC(O)O(CR⁸R⁹)_(r), (CH₂)_(r)OC(O)NR³(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)NR³C(O)O(CR⁸R⁹)_(r), (CH₂)_(r)NR³C(O)NR³(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)S(O)_(p)(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)S(O)₂(CH═CH),(CCR⁸R⁹)_(r)SO₂NR³(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)NR³SO₂(CR⁸R⁹)_(r), and(CR⁸R⁹)_(r)NR³SO₂NR³(CR⁸R⁹)_(r), provided that Z does not form a N—N,N—O, N—S, NCH₂N, NCH₂O, or NCH₂S bond with the groups to which Z isattached;

R^(1a)is absent or selected from —(CH₂)_(r)—R^(1′), —CH═CH—R^(1′),NHCH₂R^(1″), OCH₂R^(1″), SCH₂R^(1″), NH(CH₂)₂(CH₂)_(t)R^(1′),O(CH₂)₂(CH₂)_(t)R^(1′), and S(CH₂)₂(CH₂)_(t)R^(1′);

R^(1′)is selected from H, C₁₋₃ alkyl, F, Cl, Br, I, —CN, —CHO,(CF₂)_(r)CF₃, (CH₂)_(r)OR², NR²R^(2a), C(O)R^(2c), OC(O)R²,(CF₂)_(r)CO₂R^(2c), S(O)_(p)(CH₂)_(r)R^(2b), NR²(CH₂)_(r)OR²,C(═NR²C)NR²R^(2a), NR²C(O)R^(2b), NR²C(O)NHR^(2b), NR²C(O)₂R^(2a),OC(O)NR^(2a)R^(2b), C(O)NR²R^(2a), C(O)NR²(CH₂)_(r)OR², SO₂NR²R^(2a),NR²SO₂R^(2b), C₃₋₆ carbocyclic residue substituted with 0-2 R⁴, and 5-10membered heterocyclic system containing from 1-4 heteroatoms selectedfrom the group consisting of N, O, and S substituted with 0-2 R⁴;

R^(1″) is selected from H, CH(CH₂OR²)₂, C(O)R^(2c), C(O)NR²R^(2a),S(O)R^(2b), S(O)₂R^(2b), and SO₂NR²R^(2a);

R^(1b) is selected from H, C₁₋₆ alkyl, and C₁₋₆ alkyl substituted withA;

R², at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl,C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 memberedheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S substituted with 0-2 R^(4b);

R^(2a), at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl,C₃₋₆ cycloalkylmethyl substituted with 0-2 R^(4b), C₃₋₆ carbocyclicresidue substituted with 0-2 R^(4b), and 5-6 membered heterocyclicsystem containing from 1-4 heteroatoms selected from the groupconsisting of N, O, and S substituted with 0-2 R^(4b);

R^(2b), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy, C₁₋₆alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and5-6 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R^(4b);

R^(2c), at each occurrence, is selected from CF₃, OH, C₁₋₄ alkoxy, C₁₋₆alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and5-6 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R^(4b);

alternatively, R² and R^(2a), together with the atom to which they areattached, combine to form a 5 or 6 membered saturated, partiallysaturated or unsaturated ring substituted with 0-2 R^(4b)and containingfrom 0-1 additional heteroatoms selected from the group consisting of N,O, and S;

R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

R^(3a), at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

R^(3b), at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

R^(3c), at each occurrence, is selected from C₁₋₄ alkyl, and phenyl;

A is selected from:

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁴, and

5-10 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R⁴;

A¹ is H or A;

alternatively, A and A₁ and the carbon to which they are attachedcombine to form fluorene;

A² is selected from H, A, and CHA³A⁴;

A³ is selected from H, A, C₁₋₄ alkyl, and —(CH₂)_(r)NR²R^(2a);

A⁴ is H or A;

B is selected from: H, Y, and X—Y

X is selected from C₁₋₄ alkylene, —CR²(CR²R^(2b))(CH₂)_(t)—, —C(O)—,—CR²(NR^(1″)R²)—, —CR²(OR²)—, —CR²(SR²)—, —C(O)CR²R^(2a)—,—CR²R^(2a)C(O), —OS(O)₂—, —S(O)_(p)—, —S(O)_(p)CR²R^(2a)—,—CR²R^(2a)S(O)_(p)—, —S(O)₂NR²—, —NR²S(O)₂—, —NR²S(O)₂CR²R^(2a)—,—CR²R^(2a)S(O)₂NR²—, —NR²S(O)₂NR²—, —C(O)NR²—, —NR²C(O)—,—C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—, —CR²R^(2a)C(O)NR²—,—CR²R^(2a)NR²C(O)—, —NR²C(O)O—, —OC(O)NR²—, —NR²C(O)NR²—, —NR²—,—NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, —CR²R^(2a)O—, and —OCR²R^(2a)—;

Y is selected from:

(CH₂)_(r)NR²R^(2a), provided that X—Y do not form a N—N, O—N, or S—Nbond,

C₃₋₁₀ carbocyclic residue substituted with 0-2 R^(4a), and

5-10 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R^(4a);

alternatively, Z—A—B combine to form S—C₁₋₆ alkyl;

R⁴, at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², F, Cl, Br,I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),NR²C(O)R^(2b), C(O)NR²R^(2a), NR²C(O)NR²R^(2a), C(═NR²)NR²R^(2a),C(═NS(O)₂R⁵)NR²R^(2a), NHC(═NR²)NR²R^(2a), C(O)NHC(═NR²)NR²R^(2a),SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵,(CF₂)_(r)CF₃, NHCH₂R^(1″), OCH₂R^(1″), SCH₂R^(1″),N(CH₂)₂(CH₂)_(t)R^(1′), O(CH₂)₂(CH₂)_(t)R^(1′), andS(CH₂)₂(CH₂)_(t)R^(1′);

alternatively, one R⁴ is a 5-6 membered aromatic heterocycle containingfrom 1-4 heteroatoms selected from the group consisting of N, O, and S;

R^(4a), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR²,(CH₂)_(r)—F, (CH₂)_(r)—Br, (CH₂)_(r)—Cl, Cl, Br, F, I, C₁₋₄ alkyl, —CN,NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b),C(O)NR²R^(2a), C(O)NH(CH₂)₂NR²R^(2a), NR²C(O)NR²R^(2a), C(═NR²)R^(3c),C(═NR²)NR²R^(2a), NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a),NR²SO₂—C₁₋₄ alkyl, C(O)NHSO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, and(CF₂)_(r)CF₃;

alternatively, one R^(4a) is a 5-6 membered aromatic heterocyclecontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-1 R⁵;

R^(4b), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR³, F, Cl,Br, I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³,(CH₂)_(r)C(O)OR^(3c), NR³C(O)R^(3a), C(O)NR³R^(3a), NR³C(O)NR³R^(3a),C(═NR³)NR³R^(3a), NR³C (═NR³)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂NR³R^(3a),NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃, NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄alkyl, S(O)_(p)-phenyl, and (CF₂)_(r)CF₃;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenylsubstituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶;

R⁶, at each occurrence, is selected from H, OH, (CH₂)_(r)OR², halo, C₁₋₄alkyl, CN, NO₂, (CH₂)_(r)NR²R^(2a),(CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b),NR²C(O)NR²R^(2a), C(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂NR²R^(2a),and NR²SO₂C₁₋₄ alkyl;

R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, (CH₂)_(n)-phenyl, C₆₋₁₀aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenylC₁₋₄ alkoxycarbonyl;

R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and(CH₂)_(n)-phenyl;

alternatively, R⁷ and R⁸ combine to form a 5 or 6 membered saturated,ring which contains from 0-1 additional heteroatoms selected from thegroup consisting of N, O, and S;

R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl and(CH₂)_(n)-phenyl;

R¹⁰ is selected from H, phenyl substituted with 0-2 R^(4a), and naphthylsubstituted with 0-2 R^(4a);

n, at each occurrence, is selected from 0, 1, 2, and 3;

m, at each occurrence, is selected from 0, 1, and 2;

p, at each occurrence, is selected from 0, 1, and 2;

r, at each occurrence, is selected from 0, 1, 2, and 3;

s, at each occurrence, is selected from 0, 1, and 2; and,

t, at each occurrence, is selected from 0, 1, 2, and 3.

[4] In a preferred embodiment, the present invention provides a novelcompound, wherein:

G is selected from the group:

R is selected from H, Cl, F, Br, I, (CH₂)_(t)OR³, C₁₋₄ alkyl, OCF₃, CF₃,C(O)NR⁷R⁸, and (CR⁸R⁹)_(t)NR⁷R⁸;

Z is selected from a CH₂O, OCH₂, CH₂NH, NHCH₂, C(O), CH₂C(O), C(O)CH₂,NHC(O), C(O)NH, CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and NHSO₂, provided that Zdoes not form a N—N, N—C, NCH₂N, or NCH₂O bond with ring M or group A;

A is selected from one of the following carbocyclic and heterocyclicsystems which are substituted with 0-2 R⁴;

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl,morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl,benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, andisoindazolyl;

B is selected from: H, Y, and X—Y;

X is selected from C₁₋₄ alkylene, —C(O)—, —C(═NR)—, —CR²(NR²R^(2a))—,—C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —C(O)NR²—, —NR²C(O)—,—C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—, —CR²R^(2a)C(O)NR²—,—CR²R^(2a)NR²C(O)—, —NR²C(O)NR²—, —NR²—, —NR²CR²R^(2a)—, CR²R^(2a)NR²—,O, —CR²R^(2a)O—, and —OCR²R^(2a)—;

Y is NR²R^(2a) or CH₂NR²R^(2a), provided that X—Y do not form a N—N orO—N bond;

alternatively, Y is selected from one of the following carbocyclic andheterocyclic systems which are substituted with 0-2 R^(4a);

cyclopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl,pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl,pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl,isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl,benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl,indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;

alternatively, Y is selected from the following bicyclic heteroaryl ringsystems:

K is selected from O, S, NH, and N.

[5] In a more preferred embodiment, the present invention provides anovel compound, wherein:

G is selected from:

Z is C(O)CH₂ and CONH, provided that Z does not form a N—N bond withgroup A;

A is selected from phenyl, pyridyl, and pyrimidyl, and is substitutedwith 0-2 R⁴; and,

B is selected from Y, X—Y, phenyl, pyrrolidino, morpholino,1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R^(4a);

B is selected from: Y and X—Y;

X is selected from CH₂, —C(O)—, and O;

Y is NR²R^(2a) or CH₂NR²R^(2a), provided that X—Y does not form an O—Nbond;

alternatively, Y is selected from one of the following carbocyclic andheterocyclic systems which are substituted with 0-2 R^(4a);

phenyl, piperazinyl, pyridyl, pyrimidyl, morpholinyl, pyrrolidinyl,imidazolyl, and 1,2,3-triazolyl;

R², at each occurrence, is selected from H, CF₃, CH₃, benzyl, andphenyl;

R^(2a), at each occurrence, is selected from H, CF₃, CH₃, CH(CH₃)₂,cyclopropylmethyl, benzyl, and phenyl;

alternatively, R² and R^(2a) combine to form a ring system substitutedwith 0-2 R^(4b), the ring system being selected from pyrrolidinyl,piperazinyl and morpholino;

R⁴, at each occurrence, is selected from OH, (CH₂)_(r)OR², Cl, F, C₁₋₄alkyl, (CH₂)_(r)NR²R^(2a), and (CF₂)_(r)CF₃;

R^(4a)is selected from Cl, F, C₁₋₄ alkyl, CF₃, (CH₂)_(r)NR²R^(2a),S(O)_(p)R⁵, SO₂NR²R^(2a), and 1-CF₃-tetrazol-2-yl;

R^(4b), at each occurrence, is selected from OH, Cl, F, CH₃, and CF₃;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, andbenzyl;

R⁷, at each occurrence, is selected from H, CH₃, and CH₂CH₃; and,

R⁸, at each occurrence, is selected from H and CH₃.

[6] In an even further preferred embodiment, the present inventionprovides a novel compound, wherein:

A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl,2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl,2-aminophenyl, and 2-methoxyphenyl; and,

B is selected from the group: 2-CF₃-phenyl, 2-(aminosulfonyl)phenyl,2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl,1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl,2-(N,N-dimethylaminomethyl)phenyl, 2-(isopropylaminomethyl)phenyl,2-(cyclopropylaminomethyl)phenyl, 2-(N-pyrrolidinylmethyl)phenyl,2-(3-hydroxy-N-pyrrolidinylmethyl)phenyl, 4-morpholino,2-(1′-CF₃-tetrazol-2-yl)phenyl, 4-morpholinocarbonyl,1-methyl-2-imidazolyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl,2-(N,N-dimethylaminomethyl)imidazolyl, 2-methylsulfonyl-1-imidazolyland, 5-methyl-1,2,3-triazolyl.

[7] In another even more preferred embodiment, the present inventionprovides a compound of formula:

L_(n) is *CH₂NHC(O)CH₂ or *CH(R^(a))NHC(O)CH₂, the * indicates whereL_(n) is bonded to G;

R^(a) is C(O)C(O)OR³;

Z is selected from a C₁₋₄ alkylene, (CH₂)_(r)C(O), and (CH₂)_(r)S(O)₂;

R², at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2a), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2b), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃, CH₃,benzyl, and phenyl;

R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

A is C₅₋₆ carbocyclic residue substituted with 0-2 R⁴;

R⁴, at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², F, Cl, Br,I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R²C,NR²C(O)R^(2b), C(O)NR²R^(2a), C(═NR²)NR²R^(2a), NHC(═NR²)NR²R^(2a),SO₂NR²R^(2a), S(O)_(p)R⁵, and CF₃;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, andbenzyl;

p, at each occurrence, is selected from 0, 1, and 2; and,

r, at each occurrence, is selected from 0, 1, 2, and 3.

[8] In another still more preferred embodiment, the present inventionprovides a compound wherein:

L_(n) is *CH(R^(a))NHC(O)CH₂;

R^(a) is C(O)C(O)OH;

Z is selected from a CH₂, (CH₂)₂C(O), and CH₂S(O)₂;

A is cyclohexyl or phenyl and is substituted with 0-1 R⁴;

R⁴, at each occurrence, is selected from H, ═O, OR², CH₂OR², F, Cl, Br,I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),C(O)NR²R^(2a), SO₂NR²R^(2a), and CF₃; and,

r, at each occurrence, is selected from 0, 1, and 2.

[9] In another even more preferred embodiment, the present inventionprovides a compound of formula:

L_(n) is *CH₂NHC(O)CH₂ or *CH(R^(a))NHC(O)CH₂, the * indicates whereL_(n) is bonded to G;

R^(a) is C(O)C(O)OR³;

R is H or NH₂;

Z is selected from a C₁₋₄ alkylene, (CH₂)_(r)C(O), and (CH₂)_(r)S(O)₂;

R², at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2a), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2b), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃, CH₃,benzyl, and phenyl;

R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

A is a C₅₋₆ carbocyclic residue substituted with 0-2 R⁴;

R⁴, at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², F, Cl, Br,I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),NR²C(O)R^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a), S(O)_(p)R⁵, and CF₃;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, andbenzyl;

p, at each occurrence, is selected from 0, 1, and 2; and,

r, at each occurrence, is selected from 0, 1, 2, and 3.

[10] In another still more preferred embodiment, the present inventionprovides a compound wherein:

L_(n) is *CH(R^(a))NHC(O)CH₂;

R is H;

R^(a) is C(O)C(O)OH;

Z is selected from a CH₂, (CH₂)₂C(O), and CH₂S(O)₂;

A is cyclohexyl or phenyl and is substituted with 0-1 R⁴;

R⁴, at each occurrence, is selected from H, ═O, OR², CH₂OR², F, Cl, Br,I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),C(O)NR²R^(2a), SO₂NR²R^(2a), and CF₃;

r, at each occurrence, is selected from 0, 1, 2, and 3.

[11] In another even more preferred embodiment, the present inventionprovides a compound of formula:

L_(n) is *CH₂NHC(O)CH₂ or *CH(R^(a))NHC(O)CH₂, the * indicates whereL_(n) is bonded to G;

R is H or NH₂;

R^(a) is C(O)C(O)OR³;

Z is C₁₋₄ alkylene;

R², at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2a), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2b), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃, CH₃,benzyl, and phenyl;

R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

A is phenyl substituted with 0-2 R⁴;

R⁴, at each occurrence, is selected from H, (CH₂)_(r)OR², F, Cl, Br, I,C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),NR²C(O)R^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a), S(O)_(p)R⁵, and CF₃;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, andbenzyl;

p, at each occurrence, is selected from 0, 1, and 2; and,

r, at each occurrence, is selected from 0, 1, 2, and 3.

[12] In another still more preferred embodiment, the present inventionprovides a compound wherein:

L_(n) is *CH(R^(a))NHC(O)CH₂;

R is NH₂;

R^(a) is C(O)C(O)OH;

Z is CH₂;

A is phenyl substituted with 0-1 R⁴;

R⁴, at each occurrence, is selected from H, OR², CH₂OR², F, Cl, Br, C₁₋₄alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), C(O)NR²R^(2a),SO₂NR²R^(2a), and CF₃; and,

r, at each occurrence, is selected from 0, 1, and 2.

[13] In another even more preferred embodiment, the present inventionprovides a compound of formula:

L_(n) is *CH₂NHC(O) or *CH(R^(a))NHC(O) and the * indicates where L_(n)is bonded to G;

R^(a) is selected from C(O)C(C)OR³ and C(O)—A;

R^(b) is selected from H, phenyl, C₁₋₁₀ alkyl, and C₂₋₅ alkenyl;

R^(c) is selected from H and C₁₋₆ alkyl;

alternatively, R^(b) and R^(c) together are —(CH₂)₄—;

Z is (CR⁸R⁹)₁₋₄;

R², at each occurrence, is selected from H, CF₃, and C₁₋₆ alkyl;

R^(2a), at each occurrence, is selected from H, CF₃, and C₁₋₆ alkyl;

R^(2b), at each occurrence, is selected from H, CF₃, and C₁₋₆ alkyl;

R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃, CH₃,benzyl, and phenyl;

R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

A is selected from:

C₆₋₁₀ aromatic carbocyclic residue substituted with 0-2 R⁴, and

5-10 membered aromatic heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-2 R⁴;

R⁴, at each occurrence, is selected from H, (CH₂)_(r)OR², F, Cl, Br, I,C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),NR²C(O)R^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a), S(O)_(p)R⁵, and CF₃;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, andbenzyl;

R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and phenyl;

R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl and phenyl;

p, at each occurrence, is selected from 0, 1, and 2;

r, at each occurrence, is selected from 0, 1, 2, and 3.

[14] In another still more preferred embodiment, the present inventionprovides a compound wherein:

L_(n) is *CH(R^(a))NHC(O) and the * indicates where L_(n) is bonded toG;

R^(a) is C(O)C(O)OH or C(O)-(benzothiazol-2-yl);

R^(b) is selected from H, phenyl, C₁ alkyl, and C₂₋₅ alkenyl;

R^(c) is selected from H and C₁₋₆ alkyl;

alternatively, R^(b) and R^(c) together are —(CH₂)₄—;

Z is (CR⁸H)₁₋₂;

A is selected from phenyl, naphthyl, and thienyl, and A is substitutedwith 0-1 R⁴;

R⁴, at each occurrence, is selected from H, OR², CH₂OR², F, Cl, Br, I,C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),C(O)NR²R^(2a), SO₂NR²R^(2a), and CF₃;

R⁸, at each occurrence, is selected from H, methyl and phenyl; and,

r, at each occurrence, is selected from 0, 1, and 2.

[15] In another even more preferred embodiment, the present inventionprovides a compound of formula:

L_(n) is *CH₂NHC(O) or *CH(R^(a))NHC(O) and the * indicates where L_(n)is bonded to G;

R^(a) is selected from C(O)C(O)OR³ and C(O)—A;

R^(b) is selected from H, phenyl, C₁₋₁₀ alkyl, and C₂₋₅ alkenyl;

R^(c) is selected from H and C₁₋₆ alkyl;

alternatively, R^(b) and R^(c) together are —(CH₂)₄—;

R is selected from H, benzyl, C₁₋₄ alkyl, and NH₂;

Z is (CR⁸R⁹)₁₋₄;

R², at each occurrence, is selected from H, CF₃, and C₁₋₆ alkyl;

R^(2a), at each occurrence, is selected from H, CF₃, and C₁₋₆ alkyl;

R^(2b), at each occurrence, is selected from H, CF₃, and C₁₋₆ alkyl;

R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃, CH₃,benzyl, and phenyl;

R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

A is selected from:

C₆₋₁₀ aromatic ring substituted with 0-2 R⁴, and

5-10 membered aromatic heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-2 R⁴;

R⁴, at each occurrence, is selected from H, (CH₂)_(r)OR², F, Cl, Br, I,C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),NR²C(O)R^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a), S(O)_(p)R⁵, and CF₃;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, andbenzyl;

R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and phenyl;

R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl and phenyl;

p, at each occurrence, is selected from 0, 1, and 2;

r, at each occurrence, is selected from 0, 1, 2, and 3.

[16] In another still more preferred embodiment, the present inventionprovides a compound wherein:

L_(n) is *CH(R^(a))NHC(O) and the * indicates where L_(n) is bonded toG;

R^(a) is C(O)C(O)OH or C(O)-(benzothiazol-2-yl);

R^(b) is selected from H, phenyl, C₁₋₁₀ alkyl, and C₂₋₅ alkenyl;

R^(c) is selected from H and C₁₋₆ alkyl;

alternatively, R^(b) and R^(c) together are —(CH₂)₄—;

Z is (CR⁸H)₁₋₂;

A is selected from phenyl, naphthyl, and thienyl, and A is substitutedwith 0-1 R⁴;

R⁴, at each occurrence, is selected from H, OR², CH₂OR², F, Cl, Br, I,C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),C(O)NR²R^(2a), SO₂NR²R^(2a), and CF₃;

R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and phenyl;

r, at each occurrence, is selected from 0, 1, and 2.

[17] In another even more preferred embodiment, the present inventionprovides a compound of formula:

L_(n) is *CH₂NHC(O) or *CH(R^(a))NHC(O) and the * indicates where L_(n)is bonded to G;

R^(1a) is selected from —(CH₂)_(r)—R^(1′) and NHCH₂R^(1″);

R^(1′) is selected from H, OR², NR²R^(2a), and NR²SO₂(CH₂)_(r)R^(2b);

R^(1″) is selected from C(O)NR²R^(2a), S(O)₂R^(2b), and SO₂NR²R^(2a);

R², at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2a), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2b), at each occurrence, is selected from C₁₋₄ alkoxy, C₁₋₆ alkyl,benzyl, phenyl substituted with 0-2 R^(4b), and 5-6 memberedheterocyclic system containing from 1-2 heteroatoms selected from thegroup consisting of N, O, and S substituted with 0-2 R^(4b);

R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃, CH₃,benzyl, and phenyl;

alternatively, R² and R^(2a), together with the atom to which they areattached, combine to form a 5 or 6 membered saturated, partiallysaturated or unsaturated ring substituted with 0-2 R^(4b)and containingfrom 0-1 additional heteroatoms selected from the group consisting of N,O, and S;

R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

A is phenyl substituted with 0-2 R⁴;

A¹ is H or A;

alternatively, A and A₁ and the carbon to which they are attachedcombine to form fluorene;

A² is selected from H, A, and CHA³A⁴;

A³ is selected from H, A, C₁₋₄ alkyl, and —(CH₂)_(r)NR²R^(2a);

A⁴ is H or A;

R⁴, at each occurrence, is selected from H, (CH₂)_(r)OR², F, Cl, Br, I,C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),NR²C(O)R^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a), S(O)_(p)R⁵, and CF₃;

R^(4b), at each occurrence, is selected from H, (CH₂)_(r)OR², F, Cl, Br,I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),NR²C(O)R^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a), S(O)_(p)R⁵, and CF₃;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, andbenzyl;

p, at each occurrence, is selected from 0, 1, and 2;

r, at each occurrence, is selected from 0, 1, 2, and 3.

[18] In another still more preferred embodiment, the present inventionprovides a compound wherein:

L_(n) is *CH₂NHC(O) and the * indicates where L_(n) is bonded to G;

R^(1a) is selected from —(CH₂)_(r)—R^(1′) and NHCH₂R^(1″);

R^(1′) is selected from OH, NR²R^(2a), and NR²SO₂(CH₂)_(r)R^(2b);

R^(1″) is selected from C(O)NR²R^(2a), S(O)₂R^(2b), and SO₂NR²R^(2a);

R², at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2a), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2b), at each occurrence, is selected from C₁₋₄ alkoxy, C₁₋₆ alkyl,benzyl, phenyl substituted with 0-1 R^(4b), and pyrrolidinyl substitutedwith 0-1 R^(4b);

R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃, CH₃,benzyl, and phenyl;

alternatively, R² and R^(2a), together with the atom to which they areattached, combine to form a piperidine ring substituted with 0-1 R^(4b);

R⁴, at each occurrence, is selected from H, ═O, OR², CH₂OR², F, Cl, Br,I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),C(O)NR²R^(2a), SO₂NR²R^(2a), and CF₃;

R^(4b), at each occurrence, is selected from H, ═O, OH, F, Cl, C₁₋₄alkyl, and NH₂; and,

r, at each occurrence, is selected from 0, 1, and 2.

[19] In another even more preferred embodiment, the present inventionprovides a compound of formula:

L_(n) is CH₂;

R^(1a) is —(CH₂)_(r)—R^(1′);

R^(1′) is selected from H, C₁₋₃ alkyl, (CH₂)_(r)OR², NR²R^(2a),C(O)R^(2c), phenyl substituted with 0-2 R⁴, and 5-6 membered aromaticheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S substituted with 0-2 R⁴;

R², at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2a), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2b), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃, CH₃,benzyl, and phenyl;

R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

A is selected from:

C₆₋₁₀ aromatic ring substituted with 0-2 R⁴, and

5-10 membered aromatic heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-2 R⁴;

B is selected from: H, Y, and X—Y

X is selected from C₁₋₄ alkylene, —NR²—, and O;

Y is selected from:

C₆₋₁₀ aromatic ring substituted with 0-2 R^(4a), and

5-6 membered aromatic heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-2 R^(4a);

R⁴, at each occurrence, is selected from H, (CH₂)_(r)OR², F, Cl, Br, I,C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),NR²C(O)R^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a), S(O)_(p)R⁵, and CF₃;

R^(4a), at each occurrence, is selected from H, (CH₂)_(r)OR², Cl, Br, F,I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),NR²C(O)R^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a), S(O)_(p)R⁵, and CF₃;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, andbenzyl;

p, at each occurrence, is selected from 0, 1, and 2; and,

r, at each occurrence, is selected from 0, 1, 2, and 3.

[20] In another still more preferred embodiment, the present inventionprovides a compound wherein:

R^(1a) is —(CH₂)_(r)—R^(1′);

R^(1′) is selected from H, C₁₋₃ alkyl, OH, NR²R^(2a), and phenylsubstituted with 0-2 R⁴;

A is selected from:

phenyl substituted with 0-2 R⁴, naphthyl substituted with 0-2 R⁴,thienyl substituted with 0-2 R⁴, benzothienyl substituted with 0-2 R⁴,5-aza-benzothienyl substituted with 0-2 R⁴, 6-azabenzothienylsubstituted with 0-2 R⁴, and quinolinyl substituted with 0-2 R⁴;

B is selected from: H, Y, and X—Y

X is O;

Y is phenyl substituted with 0-1 R^(4a);

R⁴, at each occurrence, is selected from H, OR², CH₂OR², F, Cl, Br, I,C₁₋₄ alkyl, —CN, (CH₂)_(r)NR²R^(2a), C(O)NR²R^(2a), and CF₃;

R^(4a), at each occurrence, is selected from H, OR², CH₂OR², F, Cl, Br,I, C₁₋₄ alkyl, —CN, (CH₂)_(r)NR²R^(2a), C(O)NR²R^(2a), and CF₃; and,

r, at each occurrence, is selected from 0, 1, and 2.

[21] In another even more preferred embodiment, the present inventionprovides a compound of formula:

L_(n) is O or S;

M² is N or CR^(f);

M³ is N or CR^(d);

provided that only one of M² and M³ is N;

R^(e) is selected from H, N(CH₃)(CH₂CO₂H) and S-(5-6 membered aromaticheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S substituted with 0-2 R⁴);

R^(d) is selected from H, F, and Cl;

alternatively, R^(d) and R^(e) combine to form—NR³—C(O)—C(R^(1b)R³)—NR³— or —N═CR²—NR³—;

R^(f) is selected from H, F, and Cl;

alternatively, R^(e) and R^(f) combine to form—NR³—C(R^(1b)R³)—C(O)—NR³— or —NR³—CR²═N—;

Z is O, provided that Z does not form a N—O or NCH₂O bond with thegroups to which Z is attached;

R^(1b) is selected from H, C₁₋₆ alkyl, and C₁₋₆ alkyl substituted withA;

R², at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2a), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2b), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃, CH₃,benzyl, and phenyl;

R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

A is selected from:

C₅₋₆ carbocyclic residue substituted with 0-2 R⁴, and

5-6 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R⁴;

B is H or Y;

Y is selected from:

C₅₋₆ carbocyclic residue substituted with 0-2 R^(4a), and

5-6 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R^(4a);

R⁴, at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², F, Cl, Br,I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O) R^(2c),NR²C(O)R^(2b), C(O)NR²R^(2a), C(═NR²)NR²R^(2a), NHC(═NR²)NR²R^(2a),SO₂NR²R^(2a), and CF₃;

R^(4a), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR²,(CH₂)_(r)—F, (CH₂)_(r)—Br, (CH₂)_(r)—Cl, Cl, Br, F, I, C₁₋₄ alkyl, —CN,NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b),C(O)NR²R^(2a), C(═NR²)NR²R^(2a), NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a), andCF₃; and,

r, at each occurrence, is selected from 0, 1, 2, and 3.

[22] In another still more preferred embodiment, the present inventionprovides a compound wherein:

L_(n) is O;

R^(e) is N (CH₃) (CH₂CO₂H);

R^(d) is H or F;

alternatively, R^(d) and R^(e) combine to form—NR³—C(O)—C(R^(1b)R³)—NR³— or —N═CR²—NR³—;

R^(f) is H or F;

alternatively, R^(e) and R^(f) combine to form—NR³—C(R^(1b)R³)—C(O)—NR³— or —NR³—CR²═N—;

R^(1b) is selected from H, C₁₋₂ alkyl and benzyl;

A is phenyl substituted with 0-2 R⁴;

B is H or Y;

Y is 5 membered heterocyclic system containing from 1-2 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R^(4a);

R⁴, at each occurrence, is selected from H, C₁₋₄ alkyl, and NR²R^(2a);and,

R^(4a), at each occurrence, is selected from H, C₁₋₄ alkyl, andNR²R^(2a).

[23] In another even more preferred embodiment, the present inventionprovides a compound of formula:

L_(n) is *CH₂NHC(O)CH₂ or *CH(R^(a))NHC(O)CH₂ and the * indicates whereL_(n) is bonded to G;

R^(a) is C(O)C(O)OR³;

R, at each occurrence, is selected from H, Cl, F, Br, I, OR³, C₁₋₄alkyl, C(O)NH₂, and NH₂;

Z is selected from a C₁₋₄ alkylene and (CH₂)_(r)SO₂NR³;

R², at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2a), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃, CH₃,benzyl, and phenyl;

R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

A is selected from:

C₅₋₆ carbocyclic residue substituted with 0-2 R⁴, and

5-6 membered aromatic heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-2 R⁴;

B is selected from: H, Y, and X—Y

alternatively, when B is H, A is (phenyl)₂CH— substituted with 0-2 R⁴;

X is selected from C₁₋₄ alkylene, —C(O)—, —NR²—, and O;

Y is selected from:

C₅₋₆ carbocyclic residue substituted with 0-2 R^(4a), and

5-6 membered aromatic heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-2 R^(4a);

R⁴, at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², F, Cl, Br,I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),C(O)NR²R^(2a), SO₂NR²R^(2a), and CF₃;

R^(4a), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², Cl,Br, F, I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),C(O)NR²R^(2a), SO₂NR²R^(2a), and CF₃; and,

r, at each occurrence, is selected from 0, 1, 2, and 3.

[24] In another still more preferred embodiment, the present inventionprovides a compound wherein:

L_(n) is *CH₂NHC(O)CH₂ and the * indicates where L_(n) is bonded to G;

R, at each occurrence, is selected from H and C₁₋₄ alkyl;

Z is CH₂SO₂NR³;

A is phenyl substituted with 0-2 R⁴;

B is H;

R⁴, at each occurrence, is selected from H, (CH₂)_(r)OR², F, Cl, C₁₋₄alkyl, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), and C(O)NR²R^(2a); and,

r, at each occurrence, is selected from 0, 1, and 2.

[25] In another even more preferred embodiment, the present inventionprovides a compound of formula:

L_(n) is *CH₂NHC(O)CH₂ or *CH(R^(a))NHC(O)CH₂ and the * indicates whereL_(n) is bonded to G;

R^(a) is C(O)C(O)OR³;

R, at each occurrence, is selected from X, C₁₋₄ alkyl, and NH₂;

R^(1b) is H or C₁₋₆ alkyl;

Z is selected from a C₁₋₄ alkylene and (CH₂)_(r)S(O)_(p)(CH₂)_(r);

R², at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2a), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃, CH₃,benzyl, and phenyl;

R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

A is selected from:

C₃₋₆ carbocyclic residue substituted with 0-2 R⁴, and

5-6 membered aromatic heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-2 R⁴;

B is selected from: H, Y, and X—Y

alternatively, when B is H, A is (phenyl)₂CH— substituted with 0-2 R⁴;

X is selected from C₁₋₄ alkylene, —C(O)—, —NR²—, and O;

Y is selected from:

C₅₋₆ carbocyclic residue substituted with 0-2 R^(4a), and

5-6 membered aromatic heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-2 R^(4a);

alternatively, Z-A-B combine to form S—C₁₋₆ alkyl;

R⁴, at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², F, Cl, Br,I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),C(O)NR²R^(2a), SO₂NR²R^(2a), and CF₃;

R^(4a), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², Cl,Br, F, I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),C(O)NR²R^(2a), SO₂NR²R^(2a), and CF₃;

p is selected from 0, 1, and 2; and,

r, at each occurrence, is selected from 0, 1, 2, and 3.

[26] In another still more preferred embodiment, the present inventionprovides a compound wherein:

L_(n) is *CH₂NHC(O)CH₂ and the * indicates where L_(n) is bonded to G;

R is H or C₁₋₄ alkyl;

R^(1b) is H;

Z is CH₂, CH₂S, or CH₂S(O)₂;

A is a C₃₋₆ carbocyclic residue substituted with 0-2 R⁴;

B is H

alternatively, Z-A-B combine to form S—C₁₋₆ alkyl;

R⁴, at each occurrence, is selected from H, (CH₂)_(r)OR², F, Cl, Br,C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), C(O)NR²R^(2a),SO₂NR²R^(2a), and CF₃; and,

r, at each occurrence, is selected from 0, 1, and 2.

[27] In another even more preferred embodiment, the present inventionprovides a compound of formula:

L_(n) is *CH₂NHC(O)CH₂ or *CH(R^(a))NHC(O)CH₂ and the * indicates whereL_(n) is bonded to G;

M¹ is absent or is CHR;

R is selected from H, Cl, F, Br, I, OR³, C₁₋₄ alkyl, OCF₃, CF₃, and NH₂;

Z is C₁₋₄ alkylene;

R², at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2a), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃, CH₃,benzyl, and phenyl;

R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

A is selected from:

C₃₋₆ carbocyclic residue substituted with 0-2 R⁴, and

5-6 membered aromatic heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-2 R⁴;

R⁴, at each occurrence, is selected from H, (CH₂)_(r)OR², F, Cl, Br, I,C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), C(O)NR²R^(2a),SO₂NR²R^(2a), and CF₃; and,

r, at each occurrence, is selected from 0, 1, 2, and 3.

[28] In another still more preferred embodiment, the present inventionprovides a compound wherein:

L_(n) is *CH₂NHC(O)CH₂ and the * indicates where L_(n) is bonded to G;

M¹ is absent;

R is selected from H and C₁₋₄ alkyl;

Z is CH₂;

A is C₃₋₆ carbocyclic residue substituted with 0-1 R⁴;

R⁴, at each occurrence, is selected from H, C₁₋₄ alkyl,(CH₂)_(r)NR²R^(2a), and CF₃; and,

r, at each occurrence, is selected from 0, 1, and 2.

[29] In another even more preferred embodiment, the present inventionprovides a compound of formula:

L_(n) is *CH₂NHC(O)CH₂ or *CH(R^(a))NHC(O)CH₂ and the * indicates whereL_(n) is bonded to G;

R^(a) is C(O)C(O)OR³;

R, at each occurrence, is selected from H, Cl, F, Br, I, OR³, C₁₋₄alkyl, C(O)NH₂, and NH₂;

Z is (CHR⁸)NR³, (CHR⁸)₂NR³, and (CHR⁸)₂SO₂R³;

provided that when Z is (CHR⁸)₂NR³, then B is absent;

R², at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2a), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃, CH₃,benzyl, and phenyl;

R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

R^(3a), at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

B is H or Y;

Y is selected from:

C₅₋₆ carbocyclic residue substituted with 0-2 R^(4a), and

5-6 membered heterocyclic system containing from 1-2 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R^(4a);

R^(4a), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², Cl,Br, F, I, C₁₋₄ alkyl, —CN, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),C(O)NR²R^(2a), SO₂NR²R^(2a), and CF₃;

R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and phenyl; and,

r, at each occurrence, is selected from 0, 1, 2, and 3.

[30] In another still more preferred embodiment, the present inventionprovides a compound wherein:

L_(n) is *CH₂NHC(O)CH₂ and the * indicates where L_(n) is bonded to G;

R, at each occurrence, is selected from H and C₁₋₄ alkyl;

Z is (CH₂)₂NR³, (CHR⁸)₂NR³ or (CHR⁸)₂SO₂R³;

B is H or Y;

Y is phenyl substituted with 0-1 R⁴, pyridyl substituted with 0-1 R⁴ orN-morpholino substituted with 0-1 R⁴;

R⁴, at each occurrence, is selected from H, and C₁₋₄ alkyl;

R⁸, at each occurrence, is selected from H, methyl and phenyl; and,

r, at each occurrence, is selected from 0, 1, and 2.

[31] In another even more preferred embodiment, the present inventionprovides a compound of formula:

L_(n) is absent;

R², at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2a), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃, CH₃,benzyl, and phenyl;

X is SO₂ or SO₂ (CH═CH);

Y is selected from:

C₆₋₁₀ carbocyclic residue substituted with 0-2 R^(4a), and

5-6 membered aromatic heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-2 R^(4a);

R⁴, at each occurrence, is selected from H, ═O, OR², CH₂OR², F, Cl, Br,I, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), C(O)NR²R^(2a),SO₂NR²R^(2a), and CF₃;

R^(4a), at each occurrence, is selected from H, OR², CH₂OR², F, Cl, Br,I, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), C(O)NR²R^(2a),SO₂NR²R^(2a), and CF₃; and,

r, at each occurrence, is selected from 0, 1, 2, and 3.

[32] In another still more preferred embodiment, the present inventionprovides a compound wherein:

X is SO₂;

Y is selected from phenyl substituted with 0-2 R^(4a)and naphthylsubstituted with 0-2 R^(4a);

R⁴, at each occurrence, is selected from H, ═O, OH, CH₂OH, F, Cl, Br,C₁₋₄ alkyl, C(O)NR²R^(2a), and C(O)R^(2c);

R^(4a), at each occurrence, is selected from H, OH, CH₂OH, F, Cl, Br,C₁₋₄ alkyl, and C(O)R^(2c); and,

r, at each occurrence, is selected from 0, 1, and 2.

[33] In another even more preferred embodiment, the present inventionprovides a compound of formula:

L_(n) is absent;

R², at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2a), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃, CH₃,benzyl, and phenyl;

alternatively, R² and R^(2a), together with the atom to which they areattached, combine to form a 5 or 6 membered saturated, partiallysaturated or unsaturated ring and containing from 0-1 additionalheteroatoms selected from the group consisting of N, O, and S;

X is SO₂ or SO₂(CH═CH);

Y is selected from:

C₆₋₁₀ carbocyclic residue substituted with 0-2 R^(4a), and

5-6 membered aromatic heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-2 R^(4a);

R⁴, at each occurrence, is selected from H, ═O, OR², CH₂OR², F, Cl, Br,I, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), C(O)NR²R^(2a),SO₂NR²R^(2a), and CF₃;

R^(4a), at each occurrence, is selected from H, OR², CH₂OR², F, Cl, Br,I, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), C(O)NR²R^(2a),SO₂NR²R^(2a), and CF₃;

r, at each occurrence, is selected from 0, 1, 2, and 3.

[34] In another still more preferred embodiment, the present inventionprovides a compound wherein:

X is SO₂;

Y is phenyl substituted with 0-2 R^(4a) or naphthyl substituted with 0-2R^(4a);

R⁴, at each occurrence, is selected from H, ═O, OR², CH₂OR², F, Cl, Br,I, C₁₋₄ alkyl, NH₂, (CH₂)_(r)C(O)R^(2c), and C(O)NR²R^(2a);

R^(4a), at each occurrence, is selected from H, ═O, OR², CH₂OR², F, Cl,Br, I, C₁₋₄ alkyl, NH₂, (CH₂)_(r)C(O)R^(2c), and C(O)NR²R^(2a);

r, at each occurrence, is selected from 0, 1, 2, and 3.

[35] In another even more preferred embodiment, the present inventionprovides a compound of formula:

L_(n) is absent;

R², at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2a), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃, CH₃,benzyl, and phenyl;

alternatively, R² and R^(2a), together with the atom to which they areattached, combine to form a 5 or 6 membered saturated, partiallysaturated or unsaturated ring and containing from 0-1 additionalheteroatoms selected from the group consisting of N, O, and S;

X is SO₂ or SO₂ (CH═CH);

Y is selected from:

C₆₋₁₀ carbocyclic residue substituted with 0-2 R^(4a), and

5-6 membered aromatic heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-2 R^(4a);

R⁴, at each occurrence, is selected from H, ═O, OR², CH₂OR², F, Cl, Br,I, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), C(O)NR²R^(2a),SO₂NR²R^(2a), and CF₃;

R^(4a), at each occurrence, is selected from H, OR², CH₂OR², F, Cl, Br,I, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), C(O)NR²R^(2a),SO₂NR²R^(2a), and CF₃;

r, at each occurrence, is selected from 0, 1, 2, and 3.

[36] In another still more preferred embodiment, the present inventionprovides a compound wherein:

X is SO₂;

Y is phenyl substituted with 0-2 R^(4a)or naphthyl substituted with 0-2R^(4a);

R⁴, at each occurrence, is selected from H, ═O, OR², CH₂OR², F, Cl, Br,I, C₁₋₄ alkyl, NH₂, (CH₂)_(r)C(O)R^(2c), and C(O)NR²R^(2a);

R^(4a), at each occurrence, is selected from H, OR², CH₂OR², F, Cl, Br,I, C₁₋₄ alkyl, NH₂, (CH₂)_(r)C(O)R^(2c), and C(O)NR²R^(2a); and,

r, at each occurrence, is selected from 0, 1, and 2.

[37] In another even more preferred embodiment, the present inventionprovides a compound of formula:

Ra is C(O)—(6 membered heterocyclic system containing 1 N atom andsubstituted with 0-2 R⁴);

R², at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2a), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃, CH₃,benzyl, and phenyl;

alternatively, R² and R^(2a), together with the atom to which they areattached, combine to form a 5 or 6 membered saturated, partiallysaturated or unsaturated ring and containing from 0-1 additionalheteroatoms selected from the group consisting of N, O, and S;

A is a 10 membered bicyclic heterocyclic system containing 1 N atom andsubstituted with 0-2 R⁴;

B is H or Y;

Y is selected from:

C₃₋₆ carbocyclic residue substituted with 0-2 R^(4a), and

5-6 membered aromatic heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-2 R^(4a);

R⁴, at each occurrence, is selected from H, ═O, OR², F, Cl, Br, I, C₁₋₄alkyl, NR²R^(2a), (CH₂)_(r)C(O)R^(2c), C(O)NR²R^(2a), and CF₃;

R^(4a), at each occurrence, is selected from H, ═O, OR², F, Cl, Br, I,C₁₋₄ alkyl, NR²R^(2a), (CH₂)_(r)C(O)R^(2c), C(O)NR²R^(2a), and CF₃;

r, at each occurrence, is selected from 0, 1, 2, and 3.

[38] In a still more preferred embodiment, the present inventionprovides a compound wherein:

R^(a) is C(O)—(N-1,2,3,6-tetrahydropyridine substituted with CO₂H);

alternatively R^(a) is C(O)—(N-1,2,3,6-tetrahydropyridine substitutedwith CH₃);

A is 1,2,3,4-tetrahydroisoquinoline substituted with 1-2 R⁴;

B is H;

R⁴, at each occurrence, is selected from H, methyl, ═O, OR², F, Cl, Br,I, C₁₋₄ alkyl, NR²R^(2a), (CH₂)_(r)C(O)R^(2c), C(O)NR²R^(2a),SO₂NR²R^(2a), and CF₃;

r, at each occurrence, is selected from 0, 1, and 2.

[39] In another even more preferred embodiment, the present inventionprovides a compound of formula:

R², at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2a), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃, CH₃,benzyl, and phenyl;

alternatively, R² and R^(2a), together with the atom to which they areattached, combine to form a 5 or 6 membered saturated, partiallysaturated or unsaturated ring and containing from 0-1 additionalheteroatoms selected from the group consisting of N, O, and S;

X is OSO₂;

Y is selected from:

C₆₋₁₀ aromatic ring substituted with 0-2 R^(4a), and

5-10 membered aromatic heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-2 R^(4a);

R⁴ is H;

R^(4a), at each occurrence, is selected from H, (CH₂)_(r)OR², F, Cl, Br,I, C₁₋₄ alkyl, —CN, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),C(O)NR²R^(2a), SO₂NR²R^(2a), and CF₃; and,

r, at each occurrence, is selected from 0, 1, 2, and 3.

[40] In a still more preferred embodiment, the present inventionprovides a compound wherein:

R is methyl;

Y is selected from phenyl substituted with 0-2 R^(4a), naphtylsubstituted with 0-2 R^(4a), and quinolinyl substituted with 0-2 R^(4a);

R^(4a), at each occurrence, is selected from H, (CH₂)_(r)OR², F, Cl, Br,I, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), and CF₃; and,

r, at each occurrence, is selected from 0, 1, and 2.

[41] In another more preferred embodiment, the present inventionprovides a compound of formula:

R^(g) is selected from H, CH₂OR³, CH₂C(O)OR³, C₁₋₄ alkyl, C(O)NH₂, andNH₂;

R^(h) is selected from H, CH₂-phenyl, CH₂CH₂-phenyl, and CH═CH-phenyl;

R², at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2a), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃, CH₃,benzyl, and phenyl;

alternatively, R² and R^(2a), together with the atom to which they areattached, combine to form a 5 or 6 membered saturated, partiallysaturated or unsaturated ring and containing from 0-1 additionalheteroatoms selected from the group consisting of N, O, and S;

R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

A is selected from:

C₆₋₁₀ aromatic ring substituted with 0-2 R⁴, and

5-6 membered aromatic heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-2 R⁴;

B is H or Y;

Y is selected from:

C₆₋₁₀ aromatic ring substituted with 0-2 R^(4a), and

5-6 membered aromatic heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-2 R^(4a);

R⁴, at each occurrence, is selected from H, (CH₂)_(r)OR², F, Cl, Br, I,C₁₋₄ alkyl, —CN, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), C(O)NR²R^(2a),SO₂NR²R^(2a), S(O)_(p)R⁵, and CF₃;

R^(4a), at each occurrence, is selected from H, (CH₂)_(r)OR², Cl, Br, F,I, C₁₋₄ alkyl, —CN, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),C(O)NR²R^(2a), SO₂NR²R^(2a), S(O)_(p)R⁵, and CF₃;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, andbenzyl;

p, at each occurrence, is selected from 0, 1, and 2; and,

r, at each occurrence, is selected from 0, 1, 2, and 3.

[42] In a still more preferred embodiment, the present inventionprovides a compound wherein:

R^(g) is selected from CH₂OR³, and CH₂C(O)OCH₃;

R^(h) is selected from CH₂-phenyl, CH₂CH₂-phenyl, and CH═CH-phenyl;

A is phenyl;

B is Y;

Y is phenyl substituted with 0-2 R^(4a);

R^(4a), at each occurrence, is selected from H, OR², Cl, Br, F, I, C₁₋₄alkyl, (CH₂)_(r)NR²R^(2a), C(O)NR²R^(2a), and CF₃; and,

r, at each occurrence, is selected from 0, 1, and 2.

[43] In another more preferred embodiment, the present inventionprovides a compound of formula:

R^(i) is selected from SO₂CH₂C(O)OR³, C(O)CH₂C(O)OR³, and C(O)OR³;

X is O;

Y is pyrrolidinyl substituted with 1-2 R^(4a)or piperidinyl substitutedwith 1-2 R^(4a);

R², at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2a), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

alternatively, R² and R^(2a), together with the atom to which they areattached, combine to form a 5 or 6 membered saturated, partiallysaturated or unsaturated ring and containing from 0-1 additionalheteroatoms selected from the group consisting of N, O, and S;

R³ ₁ at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

R⁴, at each occurrence, is selected from H, F, Cl, Br, I, C₁₋₄ alkyl,NR²R^(2a), and CF₃; and,

R^(4a), at each occurrence, is selected from H, C₁₋₄ alkyl,CH₂NR²R^(2a), and C(═NR²) CH₃.

[44] In a still more preferred embodiment, the present inventionprovides a compound wherein:

R^(i) is selected from SO₂CH₂C(O)OR³ and C(O)CH₂C(O)OR³;

Y is piperidinyl substituted with 1-2 R^(4a);

R³, at each occurrence, is selected from H and C₁₋₄ alkyl;

R⁴ is H; and,

R^(4a), at each occurrence, is selected from H, C₁₋₄ alkyl,CH₂NR²R^(2a), and C(═NR²)CH₃.

[45] In another more preferred embodiment, the present inventionprovides a compound of formula:

R^(i) is selected from SO₂CH₂C(O)OR³, C(O)CH₂C(O)OR³, and C(O)OR³;

X is O;

Y is pyrrolidinyl substituted with 1-2 R^(4a)or piperidinyl substitutedwith 1-2 R^(4a);

R², at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2a), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

alternatively, R² and R^(2a), together with the atom to which they areattached, combine to form a 5 or 6 membered saturated, partiallysaturated or unsaturated ring and containing from 0-1 additionalheteroatoms selected from the group consisting of N, O, and S;

R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

R⁴, at each occurrence, is selected from H, F, Cl, Br, I, C₁₋₄ alkyl,NR²R^(2a), and CF₃; and,

R^(4a), at each occurrence, is selected from H, C₁₋₄ alkyl,CH₂NR²R^(2a), and C(═NR²)CH₃.

[46] In a still more preferred embodiment, the present inventionprovides a compound wherein:

R^(i) is selected from SO₂CH₂C(O)OR³ and C(O)CH₂C(O)OR³;

Y is piperidinyl substituted with 1-2 R^(4a);

R³, at each occurrence, is selected from H and C1-4 alkyl;

R⁴ is H; and,

R^(4a), at each occurrence, is selected from H, C₁₋₄ alkyl,CH₂NR²R^(2a), and C(═NR²)CH₃.

[47] In another more preferred embodiment, the present inventionprovides a compound of formula:

R is selected from H, C₁₋₄ alkyl, and NH₂;

R², at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2a), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

R^(2b), at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl;

alternatively, R² and R^(2a), together with the atom to which they areattached, combine to form a 5 or 6 membered saturated, partiallysaturated or unsaturated ring and containing from 0-1 additionalheteroatoms selected from the group consisting of N, O, and S;

A is selected from:

C₆₋₁₀ aromatic ring substituted with 0-2 R⁴, and

5-10 membered aromatic heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-2 R⁴;

B is Y or X-Y;

X is O;

Y is selected from phenyl substituted with 0-2 R^(4a), pyrrolidinylsubstituted with 0-2 R^(4a), and piperidinyl substituted with 0-2R^(4a);

R⁴, at each occurrence, is selected from H, OH, CH₂OH, Cl, Br, F, I,C₁₋₄ alkyl, —CN, (CH₂)_(r)NR²R^(2a), C(O)NR²R^(2a), and CF₃;

R^(4a), at each occurrence, is selected from H, OH, CH₂OH, Cl, Br, F, I,C₁₋₄ alkyl, —CN, (CH₂)_(r)NR²R^(2a), C(O)NR²R^(2a), C(═NR²)NR²R^(2a),and CF₃;

n is 0 or 1; and,

r, at each occurrence, is selected from 0, 1, 2, and 3.

[48] In a still more preferred embodiment, the present inventionprovides a compound wherein:

R is selected from H, methyl, ethyl, and NH₂;

A is phenyl substituted with 0-1 R⁴ or thienyl substituted with 0-1 R⁴;

B is Y or X-Y;

X is O;

Y is selected from phenyl substituted with 0-2 R^(4a), pyrrolidinylsubstituted with 0-2 R^(4a), and piperidinyl substituted with 0-2R^(4a);

R⁴, at each occurrence, is selected from H, OH, CH₂OH, Cl, Br, F, I,C₁₋₄ alkyl, NH₂, C(O)NH₂, and CF₃;

R^(4a), at each occurrence, is selected from H, OH, CH₂OH, Cl, Br, F, I,C₁₋₄ alkyl, NH₂, and C(═NR²)NR²R^(2a); and ,

r, at each occurrence, is selected from 0, 1, 2, and 3.

[49] In another embodiment, the present invention provides compoundsselected from the group:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

G is selected from:

R^(a) is selected from C(O)C(O)OH and C(O)(benzothiazol-2-yl);

R^(g) is selected from H, CH₂OR³, CH₂C(O)OR³, C₁₋₄ alkyl, C(O)NH₂, andNH₂;

R^(h) is selected from H, CH₂-phenyl, CH₂CH₂-phenyl, and CH═CH-phenyl;

R^(i) is selected from SO₂CH₂C(O)OH and C(O)CH₂C(O)OH, and C(O)OR³;

R, at each occurrence, is selected from H, methyl, ethyl, benzyl, andNH₂;

R², at each occurrence, is selected from H, CF₃, CH₃, benzyl, andphenyl;

R^(2a), at each occurrence, is selected from H, CF₃, CH₃, benzyl, andphenyl;

alternatively, R² and R^(2a)combine to form a ring system selected frompyrrolidinyl, piperazinyl and morpholino;

R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

Z is C(O)CH₂ or CONH;

A is selected from phenyl, pyridyl, and pyrimidyl, and is substitutedwith 0-2 R⁴; and,

B is selected from Y, X—Y, phenyl, pyrrolidino, morpholino,1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R^(4a);

R⁴, at each occurrence, is selected from OH, (CH₂)_(r)OR², halo, C₁₋₄alkyl, (CH₂)_(r)NR²R^(2a), and (CF₂)_(r)CF₃;

R^(4a) is selected from C₁₋₄ alkyl, CF₃, S(O)₂R⁵, SO₂NR^(2a), and1-CF₃-tetrazol-2-yl;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, andbenzyl;

X is CH₂ or C(O);

Y is selected from NR²R^(2a) and CH₂NR²R^(2a);

p is selected from 0, 1, and 2; and,

r is selected from 0, 1, and 2.

In another embodiment, the present invention provides novelpharmaceutical compositions, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of presentinvention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method fortreating or preventing a thromboembolic disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a compound of the present invention or a pharmaceuticallyacceptable salt form thereof.

Definitions

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated. Allprocesses used to prepare compounds of the present invention andintermediates made therein are considered to be part of the presentinvention.

“Substituted” is intended to indicate that one or more hydrogens on theatom indicated in the expression using “substituted” is replaced with aselection from the indicated group(s), provided that the indicatedatom's normal valency is not exceeded, and that the substitution resultsin a stable compound. When a substituent is keto (i.e., ═O) group, then2 hydrogens on the atom are replaced.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium. Isotopes of carbon include C-13 and C-14.

When any variable (e.g., R⁶) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R⁶, then saidgroup may optionally be substituted with up to two R⁶ groups and R⁶ ateach occurrence is selected independently from the definition of R⁶.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “alkyl” or “alkylene” is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. C₁₋₁₀ alkyl (or alkylene),is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkylgroups. Examples of alkyl include, but are not limited to, methyl,ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, ands-pentyl. “Haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 or more halogen(for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples ofhaloalkyl include, but are not limited to, trifluoromethyl,trichloromethyl, pentafluoroethyl, and pentachloroethyl. “Alkoxy”represents an alkyl group as defined above with the indicated number ofcarbon atoms attached through an oxygen bridge. C₁₋₁₀ alkoxy, isintended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkoxygroups. Examples of alkoxy include, but are not limited to, methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy,and s-pentoxy. “Cycloalkyl”, is intended to include saturated ringgroups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C₃₋₇cycloalkyl, is intended to include C₃, C₄, C₅, C₆, and C₇ cycloalkylgroups. “Alkenyl” or “alkenylene” is intended to include hydrocarbonchains of either a straight or branched configuration and one or moreunsaturated carbon-carbon bonds which may occur in any stable pointalong the chain, such as ethenyl and propenyl. C₂₋₁₀ alkenyl (oralkenylene), is intended to include C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, andC₁₀ alkenyl groups. “Alkynyl” or “alkynylene” is intended to includehydrocarbon chains of either a straight or branched configuration andone or more triple carbon-carbon bonds which may occur in any stablepoint along the chain, such as ethynyl and propynyl. C₂₋₁₀ alkynyl (oralkynylene), is intended to include C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, andC₁₀ alkynyl groups.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, and sulfate.

As used herein, “carbocycle” or “carbocyclic group” is intended to meanany stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9,10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may besaturated, partially unsaturated, or aromatic. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane,[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl,and tetrahydronaphthyl.

As used herein, the term “heterocycle” or “heterocyclic group” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated,partially unsaturated or unsaturated (aromatic), and which consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, NH, O and S and including any bicyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring. The nitrogen and sulfur heteroatoms may optionally beoxidized. The heterocyclic ring may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Theheterocyclic rings described herein may be substituted on carbon or on anitrogen atom if the resulting compound is stable. A nitrogen in theheterocycle may optionally be quaternized. It is preferred that when thetotal number of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1. Asused herein, the term “aromatic heterocyclic group” or “heteroaryl” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring whichconsists of carbon atoms and 1, 2, 3, or 4 heterotams independentlyselected from the group consisting of N, NH, O and S. It is to be notedthat total number of S and O atoms in the aromatic heterocycle is notmore than 1.

Examples of heterocycles include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl. Also included are fused ring and spiro compounds containing,for example, the above heterocycles.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

“Prodrugs” are intended to include any covalently bonded carriers whichrelease the active parent drug according to formula (I) in vivo whensuch prodrug is administered to a mammalian subject. Prodrugs of acompound of formula (I) are prepared by modifying functional groupspresent in the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound. Prodrugs include compounds of formula (I) wherein a hydroxy,amino, or sulfhydryl group is bonded to any group that, when the prodrugor compound of formula (I) is administered to a mammalian subject,cleaves to form a free hydroxyl, free amino, or free sulfhydryl group,respectively. Examples of prodrugs include, but are not limited to,acetate, formate and benzoate derivatives of alcohol and aminefunctional groups in the compounds of formula (I), and the like.Preferred prodrugs are amidine prodrugs wherein D is C(═NR⁷)NH₂ or itstautomer C(═NH)NHR⁷ and R⁷ is selected from OH, C₁₋₄ alkoxy, C₆₋₁₀aryloxy, C₁₋₄ alkoxycarbonyl, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, and C₆₋₁₀arylcarbonyloxy C₁₋₄ alkoxycarbonyl. More preferred prodrugs are whereR⁷ is OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl, andmethylcarbonyloxymethoxycarbonyl.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention or an amount of the combination ofcompounds claimed effective to inhibit factor Xa or thrombin or treatdiseases related to factor Xa or thrombin in a host. The combination ofcompounds is preferably a synergistic combination. Synergy, as describedfor example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984),occurs when the effect (in this case, inhibition of factor Xa orthrombin) of the compounds when administered in combination is greaterthan the additive effect of the compounds when administered alone as asingle agent. In general, a synergistic effect is most clearlydemonstrated at suboptimal concentrations of the compounds. Synergy canbe in terms of lower cytotoxicity, increased antiviral effect, or someother beneficial effect of the combination compared with the individualcomponents.

Synthesis

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. It will be understood by those skilledin the art of organic synthesis that the functionality present on themolecule should be consistent with the transformations proposed. Thiswill sometimes require a judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention. It will also berecognized that another major consideration in the planning of anysynthetic route in this field is the judicious choice of the protectinggroup used for protection of the reactive functional groups present inthe compounds described in this invention. An authoritative accountdescribing the many alternatives to the trained practitioner is Greeneand Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).All references cited herein are hereby incorporated in their entiretyherein by reference.

Compounds of the above formulas can be prepared by couplingcorresponding acid and amine precursors. The acid precursors can beprepared as shown in W098/28326, WO 98/09987, WO /28326, WO96/19483, andWO98/05333, the contents of which are incorporated herein by reference.The G—CH(R^(a))NH₂ precursors can be prepared as shown in theabove-identified publications or as shown in the present application.

Compounds of the above formulas can be prepared by couplingcorresponding acid and amine precursors. The acid precursors can beprepared as shown in WO98/05333, the contents of which are incorporatedherein by reference. The G—CH(R^(a))NH₂ precursors can be prepared asshown in the above-identified publications or as shown in the presentapplication.

Compounds of the above formula can be prepared by coupling thecorresponding acid and amine precursors. The acid precursors can beprepared as shown in U.S. Pat. No. 5,798,377, the contents of which areincorporated herein by reference. The G—CH₂NH₂ precursors can beprepared as shown in the above-identified publication or as shown in thepresent application.

Compounds of the above formulas can be prepared by couplingcorresponding G—CH₂NH₂ and ester-aldehyde precursors. The ester-aldehydeprecursors can be prepared as shown in WO 98/05333, the contents ofwhich are incorporated herein by reference. The G—CH₂NH₂ precursors canbe prepared as shown in the above-identified publication or as shown inthe present application.

Compounds of the above formula can be prepared by coupling correspondingG-leaving group and alcohol-pyridyl or thiol-pyridyl precursors. Thealcohol and thio precursors can be prepared as shown in U.S. Pat. No.5,693,641, WO96/28427, WO97/29067, WO98/07725, and WO98/15547, thecontents of which are incorporated herein by reference. The G-leavinggroup precursors can be prepared as shown in the above-identifiedpublications or as shown in the present application. Alternatively, thecompounds of the above formula can be prepared by displacing a leavinggroup from the pyridyl precursor with the corresponding G—OH precursor.Leaving groups for this type of coupling can be SCH₃ or SO₂CH₃.

Compounds of the above formula can be prepared by coupling correspondingacid and amine precursors. The acid precursors can be prepared as shownin WO97/30708, the contents of which are incorporated herein byreference. The G—CH₂NH₂ precursors can be prepared as shown in theabove-identified publication or as shown in the present application.

Compounds of the above formula can be prepared by coupling correspondingacid and amine precursors. The acid precursors can be prepared as shownin WO98/31670, the contents of which are incorporated herein byreference. The G—CH₂NH₂ precursors can be prepared as shown in theabove-identified publication or as shown in the present application.

Compounds of the above formula can be prepared by X couplingcorresponding acid and amine precursors. The acid precursors can beprepared as shown in WO97/40024, the contents of which are incorporatedherein by reference. The G—CH₂NH₂ precursors can be prepared as shown inthe above-identified publication or as shown in the present application.

Compounds of the above formula can be prepared by coupling correspondingacid and amine precursors. The acid precursors can be prepared as shownin WO98/17274, the contents of which are incorporated herein byreference. The G—CH₂NH₂ precursors can be prepared as shown in theabove-identified publication or as shown in the present application.

Compounds of the above formula can be prepared by coupling correspondingG-benzoic acid and piperazine precursors. The G-benzoic acid precursorscan be prepared similarity to the methods shown in WO98/21188, thecontents of which are incorporated herein by reference. For example, theG-benzoic acid precursors can be prepared by coupling an activated G(e.g., a metallated ring) with a leaving group-benzoic acid (e.g.,halo-benzoic acid) as shown in the above-identified publication. Thepiperazine precursors can be prepared by coupling of the desiredpiperizine with the desired X—Y group, wherein X contains a leavinggroup, as shown in the above-identified application or in the presentapplication.

Compounds of the above formulas can be prepared by couplingcorresponding benzoic acid and piperazine precursors. The G-piperidinylacid or G-piperazinyl acid precursors can be prepared similarity to themethods shown in WO96/10022, the contents of which are incorporatedherein by reference. For example, the G-piperidinyl acid orG-piperazinyl acid precursors can be prepared by coupling a G-leavinggroup (e.g., G-halogen) with a piperidinyl acid or piperazinyl acid asshown in the above-identified publication. The piperidine and piperazineprecursors can be prepared by coupling of the desired piperizine withthe desired X—Y group, wherein X contains a leaving group, as shown inthe above-identified application or in the present application.

Compounds of the above formula can be prepared by coupling correspondingsulfonic acid and amine precursors. The sulfonic acid precursors can beprepared as shown in WO96/33993, the contents of which are incorporatedherein by reference. The G—CH₂CH(R^(a))NH₂ precursors can be prepared asshown in the above-identified publication or as shown in the presentapplication.

Compounds of the above formula can be prepared by coupling correspondingG—CHO or G—CH₂Br and (R^(g))CH₂CH₂(R^(h))N(R³)C(O)—A—B precursors. The(R^(g))CH₂CH₂(R^(h))N(R³)C(O)—A—B precursors can be prepared as shown inWO97/24118, the contents of which are incorporated herein by reference.The G—CHO and G—CH₂Br precursors can be prepared as shown in theabove-identified publication or as shown in the present application.

Compounds of the above formula can be prepared by coupling correspondingG—(CH₂)₃-leaving group and ester precursors. The ester precursors can beprepared as shown in EP/0540051, the contents of which are incorporatedherein by reference. The G—(CH₂)₃-leaving group precursors can beprepared as shown in the above-identified publication or otherpublications described herein or as shown in the present application.

Compounds of the above formula when G contains an amine linker can beprepared by displacing a leaving group off of the remainder of themolecule with corresponding G-amine precursor. The remainder of themolecule can be prepared as shown in JP10/1467, the contents of whichare incorporated herein by reference. The G—NH₂ precursors can beprepared as shown in the above-identified publications or as shown inthe present application.

Compounds of the above formula can be prepared by coupling correspondingG—(CH₂)₃-leaving group and phenol precursors. The phenol precursors canbe prepared as shown in W097/36580, the contents of which areincorporated herein by reference or as shown in the present application.The G—(CH₂)₃-leaving group precursors can be prepared as shown in theabove-identified publication or other publications described herein oras shown in the present application.

Compounds of the above formulas can be prepared by couplingcorresponding aniline and G—(CH₂)₃-leaving group or G—(CH₂)₂CO₂Hprecursors. The aniline precursors can be prepared as shown inEP/0540051, JP10/1467, and WO96/16940, the contents of which areincorporated herein by reference. The G—(CH₂)₃-leaving group orG—(CH₂)₂CO₂H precursors can be prepared as shown in the above-identifiedpublication or other publications described herein or as shown in thepresent application.

Many of the compounds of the present invention can be prepared fromG—NH₂ where G represents a residue which is either the P1 residuedescribed above, a suitably protected form of the P1 residue, or anintermediate which can be transformed at a later stage of the synthesisinto the P1 residue. Scheme I describes procedures by which the aminoresidue of G—NH₂ can be transformed into a variety of differentfunctionalities which are useful for assembling the compounds of thepresent invention. G—NH₂ I can be diazotized with sodium nitrite in thepresence of aqueous sulfuric acid to produce the hydroxy derivative II.Diazotization of I in acidic media followed by treatment with copper (I)bromide affords the bromo derivative III. The bromo derivative is a veryuseful intermediate for further functionalization. Treatment of III withmagnesium metal generates a Grignard reagent which can react withsuitably protected bromoglycinate derivatives to afford amino acidderivatives IV. There are a wide variety of methods available forintroducing simple carbon-atom based functionality starting with bromideIII. Transmetallation with an organolithium reagent such astert-butyllithium or n-butyllithium is readily accomplished at lowtemperature. The formed organolithium species can react with a widevariety of electrophiles. For example, reaction with dimethylformamideproduces the aldehyde derivative V, while reaction with an alkylchloroformate or an alkyl cyanoformate produces an ester derivative. Theester functionality can be reduced with a variety of hydride reducingagents such as lithium aluminum hydride or diisobutylaluminum hydride toafford the alcohol VI. The alcohol VI can also be prepared by reductionof aldehyde V, such as with sodium borohydride. The bromide III can alsoreact through palladium-mediated processes. For example, reaction of IIIwith an alcohol or amine and a catalyst such astetrakis-triphenylphosphine palladium under a carbon monoxide atmosphereleads to esters G—CO₂R or amides G—CONR₂ via a carbonyl insertionreaction. A particularly useful amide G—CONR₂ available by thisprocedure is the N-methyl-N-methoxy amide, obtained whenN-methyl-N-methoxyamine is used in the carbonyl insertion reaction. Thisamide is readily reduced to aldehyde V with hydride reducing agents suchas diisobutylaluminum hydride. The alcohol VI, readily available by avariety of methods as described above can be converted to the bromidederivative VII by many methods, such as by treatment with carbontetrabromide and triphenylphosphine. Another method for the preparationof bromide VII, not shown in Scheme I, involves the radical brominationof an intermediate G—CH₃, which is readily available by methods known tothose skilled in the art of organic synthesis. This radical brominationis readily accomplished by treating G—CH₃ with N-bromosuccinimide inrefluxing carbon tetrachloride in the presence of a radical initiatorsuch as AIBN. The bromide VII is a particularly useful intermediate forthe preparation of the compounds of the present invention. Displacementof the bromide can be accomplished by treatment with sodium or potassiumcyanide in a solvent such as DMF or DMSO at room temperature or elevatedtemperature to give a cyano derivative. Reduction of the nitrile, suchas by catalytic hydrogenation or by treatment with sodium borohydrideand cobalt (II) chloride, gives the amino derivative VIII. The bromidecan also be displaced by appropriate N-protected glycinates, such asN-(diphenylmethylene)glycine ethyl ester, to give the amino acidderivatives IX. This reaction is accomplished by heating VII and theglycinate in the presence of a base such as potassium carbonate and aquaternary ammonium salt such as tetrabutylammonium bromide in a solventsuch as acetonitrile. The bromide can also be displaced with sodiumazide in a solvent such as DMF or DMSO at elevated temperatures to givean azide intermediate. The azide is readily reduced by a variety ofreducing agents, such as by catalytic hydrogenation or by tin (II)chloride, to afford the amino derivative XI. A variety of other methodsare available for the preparation of the amino derivative XI. Forexample, reductive amination of aldehyde V with ammonium acetate andsodium cyanoborohydride affords XI. Alternatively, the amine G—NH₂ I canbe diazotized as described above and reacted with copper (I) cyanide toafford the nitrile X. The nitrile can be reduced to form amine XI by avariety of methods, such as by catalytic hydrogenation or by reductionwith sodium borohydride in the presence of cobalt (II) chloride. Avariety of other methods for the preparation of the intermediatesdescribed in Scheme I are available and are known to those skilled inthe art. The particular method used for the preparation of the requiredintermediates will depend on additional functionality present on group“G”, and it will be appreciated by those skilled in the art that certainprotecting group strategies may be required and that reaction conditionsand the order of steps may require modification.

As an illustration, in Scheme II is shown how the chemistry in Scheme Ican be applied to the preparation of intermediates in which the group Gis a suitably protected 3-aminobenzisoxazole, prepared as described inSchemes XXVIII and XXXI. As described previously, the amino group of XIIcan be transformed into the corresponding hydroxyl, cyano or bromidederivatives XIII, XXI, and XIV, respectively, via its derived diazoniumion. The bromide is a particularly useful intermediate and can betransformed by a wide variety of anionic or palladium-mediated processesinto amino acid derivatives XV, aldehydes XVI and alcohols XVII, inaddition to various ester and amide derivatives. The aldehyde andalcohol derivatives are useful for the preparation of the bromide XVIII,which in turn can be transformed into a wide variety of intermediatessuch as amines XIX and XXII, and amino acid derivatives XX.

Alternatively, in the case of the 3-aminobenzisoxazole derivativesdescribed in Scheme II, it is also possible to form theaminobenzisoxazole ring at a later stage of the synthesis, therebycarrying out the chemistry described in Scheme II on a latent form ofthe aminobenzisoxazole G group, as shown in Scheme III. The amine XXIIIcorresponds to G—NH₂ where G represents an intermediate which can betransformed at a later stage of the synthesis into the P1 residue. Inthe aminobenzisoxazole case, X can represent cyano, which is the desiredgroup for formation of the aminobenzisoxazole ring, or X can represent agroup such as Br, NH₂, NO₂, ester, amide, etc., which can easily beconverted into a cyano group by a variety of methods known to thoseskilled in the art. The intermediate XXIII can be converted into XXIV,where R represents the remainder of the inhibitor, by methods describedin other schemes, and XXIV can be converted into the aminobenzisoxazoleXXV as described previously.

In Scheme IV is shown how the chemistry in Scheme II can be applied to aparticularly preferred compound of the present invention. Alkylation ofN-(diphenylmethylene)glycine ethyl ester with bromide XVIII usingpotassium carbonate as base and tetrabutylammonium bromide inacetonitrile affords, after deprotection, aminoester XXVI. This racemiccompound can be resolved, preferably by selective hydrolysis of asuitable N-protected derivative with an esterase such as α-chymotrypsin,to afford, after reesterification and N-deprotection, the preferred(S)-aminoester XXVII. Coupling with the sulfonyl chloride XXVIII andsubsequent removal of the trifluoracetate group under basic conditions,N-methylation via reductive amination with paraformaldehyde and sodiumtriacetoxyborohydride, and basic ester hydrolysis affords XXIX.Formation of the acid chloride of XXIX with oxalyl chloride is followedby addition of the tetrahydropyridine XXX to produce an amide.N-deprotection and basic ester hydrolysis yields the preferred compoundXXXI.

A can be prepared via the methodology outlined in Scheme V below.

Removal of the amino protecting group followed by further manipulationcan afford key starting materials wherein the amino is a benzylamine oralpha-amino acid or all analogs stated earlier. The starting materialcan also be obtained from intermediate 4 via an SN2 type displacement ofthe o-tosylate. Decarboxylation of intermediate 3 affords the ketoneanalog which also can be further manipulate to afford additionalstarting materials G. Coupling of analogs such as intermediate 7 viastandard techniques followed by displacement of the phenoxy pyridine viastandard techniques known to those in the art should afford thecompounds of formula A. Chiral compounds can be separated via chiralHPLC techniques or by co-crystallization methods with a known chiralprecursor.

Compounds wherein G is of formula B as shown above can be prepared asshown in Scheme VI.

Via this scheme amino intermediates such as 3(B) and phenoxy analogs 6and 7 can be obtained easily via the methods previously described. Theseintermediates can be further coupled to requisite precursors followed byconversion of the phenoxy group to an amino via standard techniques toafford the amino-pyridyl compounds of formula 1-3.

The unsaturated analogs can be prepared according to Scheme VII.

Intermediate 3 can be further manipulated to afford other Gintermediates via methods described previously. In a similar fashion theother unsaturated analog can be prepared via Scheme VIII shown below.

Conversion of intermediate 1-3 can be done via standard techniques knownto those in the art of organic synthesis. Analog 3 can be furthercoupled to various intermediates to afford compounds of formula 1-3 anillustrative example is shown below in Scheme IX.

Scheme X exemplifies the preparation of compounds wherein G is2-aminobenzoisoxazole.

The Cbz-protected diaminobenzoisoxazole undergoes reductive dialkylationwith the dialdehyde prepared by the ozonolysis of the known3-carbomethoxy cyclopentene followed by hydrolysis of the ester to theN-aryl isonipecotic acid. Activation of the carboxylic acid group bytreatment with carbonyldiimidazole followed by quenching withpiperazine((6-chloro)naphth-2-yl)sulfonamide and removal of the Cbzprotecting group gives the target compound.

Scheme XI describes the preparation of 3-aminobenzofuran intermediates.

4-benzyloxy-2(1H)-pyridone (available from Aldrich) can be converted tothe aminopyridine derivative using standard procedures known to thepractitioners of the art. Debenzylation, coupling withbromoethylacetate, followed by basic hydrolysis affords an intermediatethat undergoes the Friedel-Crafts acylation.

Scheme XII describes the preparation of indole intermediates.

Scheme XIII describes the preparation of 3-halo-4-aminobenzothiopheneintermediates.

Scheme XIV describes the preparation of1-substituted-7-amino-azabenzimidazole intermediates.

Scheme XV describes the preparation of2-substituted-7-amino-azabenzimidazole intermediates.

Scheme XVI describes the preparation compounds wherein G is a3-amino-5-benzisoxazoline.

Scheme XVII describes the preparation of 5-aminobenzisoxazoleintermediates.

Synthesis of 5-aminobenzisoxazoles in which the 3-position may be aprotected amine could be accomplished starting from the commerciallyavailable 3-cyano-4-fluoronitrobenzene. Displacement of flourine withacetohydroxamic acid under basic conditions followed by ring closure bysubsequent addition to the nitrile would yield the benzisoxazole core.Suitable protection and reduction of the aryl nitro group would providethe desired compound.

Scheme XVIII describes the preparation of 5-aminoindazole intermediates.

Synthesis of 5-aminoindazoles in which the 3-position may be a protectedamine could be accomplished starting from the commercially available3-cyano-4-fluoronitrobenzene. Displacement of flourine with hydrazinefollowed by ring closure by subsequent addition to the nitrile wouldyield the indazole core. Suitable protection and reduction of the arylnitro group would provide the desired compound.

Scheme XIX describes the preparation of 5-aminobenzisothiazoleintermediates.

Synthesis of 5-aminobenzisothiazoles in which the 3-position may be aprotected amine could be accomplished starting from the commerciallyavailable 2-benzylthio-5-nitrobenzonitrile. Conversion of the arylnitrile to benzamidine, sulfoxide formation and ringclosure/debenzylation would yield the benzisothiazole core. Suitableprotection and reduction of the aryl nitro group would provide thedesired compound.

Scheme XX describes the preparation of6-aminobenzisoxazoleintermediates.

Synthesis of 6-aminobenzisoxazoles in which the 3-position may be aprotected amine could be accomplished starting from commerciallyavailable 2-fluoro-4-nitrobenzoic acid. Conversion of carboxylic acid tonitrile via standard manipulations would give2-fluoro-4-nitrobenzonitrile. Displacement of flourine withacetohydroxamic acid under basic conditions followed by ring closure bysubsequent addition to the nitrile would yield the benzisoxazole core.Suitable protection and reduction of the aryl nitro group would providethe desired compound.

Scheme XXI describes the preparation of 5-aminoindazole intermediates.

Synthesis of 5-aminoindazoles in which the 3-position may be a protectedamine could be accomplished starting from 2-fluoro-4-nitrobenzonitrilewhose synthesis is described elsewhere in this patent. Displacement offlourine with hydrazine followed by ring closure by subsequent additionto the nitrile would yield the indazole core. Suitable protection andreduction of the aryl nitro group would provide the desired compound.

Scheme XXII describes the preparation of 6-aminobenzisothiazoleintermediates.

Synthesis of 6-aminobenzisothiazoles in which the 3-position may be aprotected amine could be accomplished starting from2-fluoro-4-nitrobenzonitrile whose synthesis is described elsewhere inthis patent. Displacement of flourine with benzylthio anion yields2-benzylthio-4-nitrobenzonitrile. Conversion of the aryl nitrile tobenzamidine, sulfoxide formation and ring closure/debenzylation wouldyield the benzisothiazole core. Suitable protection and reduction of thearyl nitro group would provide the desired compound.

Scheme XXIII describes the preparation of 6-aminoisoindoleintermediates.

Synthesis of 6-aminoisoindoles in which the 1-position may be aprotected amine could be accomplished starting from commerciallyavailable 2-cyano-4-nitrotoluene. Bromination of tolyl methyl to give abenzyl bromide followed by displacement with azide and reduction tobenzylamine would cyclize to the isoindole core. Suitable protection andreduction of the aryl nitro group would provide the desired compound.

Scheme XXIV describes the preparation of 5-aminoisoindole intermediates.

Synthesis of 5-aminoisoindoles in which the 1-position may be aprotected amine could be accomplished starting from commerciallyavailable 2-cyano-5-nitrotoluene. Bromination of tolyl methyl to give abenzyl bromide followed by displacement with azide and reduction tobenzylamine would cyclize to the isoindole core. Suitable protection andreduction of the aryl nitro group would provide the desired compound.

Scheme XXV describes the preparation of 2-aminoindole derivatives aintermediates.

Synthesis of the desired compounds in which the 4-position may be aprotected amine could be accomplished starting from the commerciallyavailable furan or thiophene. Using literature methods (J. Med. Chem.1989, 32, 1147) one could obtain the 2-nitro-4-chloro-furo orthieno<3,2-c>pyridine. Displacement of the 4-chloro with phenoxide thenconversion to 4-amino followed by suitable protection and reduction ofthe aryl nitro group would provide the desired compound.

Scheme XXVI describes the preparation of2-amino-1-H-pyrrolo[3,2-c]pyridine intermediates.

Synthesis of 2-amino-1-H -pyrrolo[3,2-c]pyridine in which the 4-positionmay be a protected amine could be accomplished starting from thecommercially available pyrrole-2-carboxaldehyde. Nitration andprotection of pyrrole nitrogen with P1 would afford the nitro/aldehydeintermediate. Using literature methods (J. Med. Chem. 1989, 32, 1147)one could obtain the 2-nitro-4-chloro-pyrrolo[3,2-c]pyridine.Displacement of the 4-chloro with phenoxide then conversion to 4-aminofollowed by suitable protection and reduction of the aryl nitro groupwould provide the desired compound.

Scheme XXVII describes the preparation compounds wherein G is a3-amino-5-benzisoxazolinyl propyl group.

BOC-Protected aminobenzisoxazolemethylbromide can be reacted with thelithium salt of acetonitrile to give the nitrile. The nitrile can befurther reacted in a similar fashion as in WO96/16940 to give thedesired compound.

The A-B moieties of the present can be prepared by methods known tothose of skill in the art. For example, preparation of the “A-B of thepresent invention moieties can follow the same methods described inWO97/23212, WO97/30971, WO97/38984, WO98/01428, WO98/06694, WO98/28269,WO98/28282, WO98/57934, WO98/57937, and WO98/57951, the contents ofwhich are incorporated herein by reference.

Utility

The compounds of this invention are useful as anticoagulants for thetreatment or prevention of thromboembolic disorders in mammals. The term“thromboembolic disorders” as used herein includes arterial or venouscardiovascular or cerebrovascular thromboembolic disorders, including,for example, unstable angina, first or recurrent myocardial infarction,ischemic sudden death, transient ischemic attack, stroke,atherosclerosis, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary and cerebral arterialthrombosis, cerebral embolism, kidney embolisms, and pulmonaryembolisms. The anticoagulant effect of compounds of the presentinvention is believed to be due to inhibition of factor Xa, thrombin, orboth.

The effectiveness of compounds of the present invention as inhibitors offactor Xa can be determined using purified human factor Xa and syntheticsubstrate. The rate of factor Xa hydrolysis of chromogenic substrateS2222 (Kabi Pharmacia, Franklin, Ohio) can be measured both in theabsence and presence of compounds of the present invention. Hydrolysisof the substrate resulted in the release of pNA, which can be monitoredspectrophotometrically by measuring the increase in absorbance at 405nM. A decrease in the rate of absorbance change at 405 nm in thepresence of inhibitor is indicative of enzyme inhibition. The results ofthis assay are expressed as inhibitory constant, K_(i).

Factor Xa determinations were made in 0.10 M sodium phosphate buffer, pH7.5, containing 0.20 M NaCl, and 0.5% PEG 8000. The Michaelis constant,K_(m), for substrate hydrolysis can be determined at 25° C. using themethod of Lineweaver and Burk. Values of K_(i) were determined byallowing 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, SouthBend, Ind.) to react with the substrate (0.20 mM-1 mM) in the presenceof inhibitor. Reactions were allowed to go for 30 minutes and thevelocities (rate of absorbance change vs time) were measured in the timeframe of 25-30 minutes. The following relationship can be used tocalculate K_(i) values:

(v_(o)−v_(s))/v_(s)=I/(K_(i)(1+S/K_(m)))

where:

v_(o) is the velocity of the control in the absence of inhibitor;

v_(s) is the velocity in the presence of inhibitor;

I is the concentration of inhibitor;

K_(i) is the dissociation constant of the enzyme:inhibitor complex;

S is the concentration of substrate;

K_(m) is the Michaelis constant.

Compounds tested in the above assay are considered to be active if theyexhibit a K_(i) of ≦10 μM. Preferred compounds of the present inventionhave K_(i)'s of ≦1 μM. More preferred compounds of the present inventionhave K_(i)'s of ≦0.1 μM. Even more preferred compounds of the presentinvention have K_(i)'s of ≦0.01 μM. Still more preferred compounds ofthe present invention have K_(i)'s of ≦0.001 μM.

The antithrombotic effect of compounds of the present invention can bedemonstrated in a rabbit arterio-venous (AV) shunt thrombosis model. Inthis model, rabbits weighing 2-3 kg anesthetized with a mixture ofxylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used. Asaline-filled AV shunt device is connected between the femoral arterialand the femoral venous cannulae. The AV shunt device consists of a pieceof 6-cm tygon tubing which contains a piece of silk thread. Blood willflow from the femoral artery via the AV-shunt into the femoral vein. Theexposure of flowing blood to a silk thread will induce the formation ofa significant thrombus. After forty minutes, the shunt is disconnectedand the silk thread covered with thrombus is weighed. Test agents orvehicle will be given (i.v., i.p., s.c., or orally) prior to the openingof the AV shunt. The percentage inhibition of thrombus formation isdetermined for each treatment group. The ID50 values (dose whichproduces 50% inhibition of thrombus formation) are estimated by linearregression.

The compounds of formula (I) may also be useful as inhibitors of serineproteases, notably human thrombin, plasma kallikrein and plasmin.Because of their inhibitory action, these compounds are indicated foruse in the prevention or treatment of physiological reactions, bloodcoagulation and inflammation, catalyzed by the aforesaid class ofenzymes. Specifically, the compounds have utility as drugs for thetreatment of diseases arising from elevated thrombin activity such asmyocardial infarction, and as reagents used as anticoagulants in theprocessing of blood to plasma for diagnostic and other commercialpurposes.

Compounds of the present invention can be shown to be direct actinginhibitors of the serine protease thrombin by their ability to inhibitthe cleavage of small molecule substrates by thrombin in a purifiedsystem. In vitro inhibition constants were determined by the methoddescribed by Kettner et al. in J. Biol. Chem. 265, 18289-18297 (1990),herein incorporated by reference. In these assays, thrombin-mediatedhydrolysis of the chromogenic substrate S2238 (Helena Laboratories,Beaumont, Tex.) can be monitored spectrophotometrically. Addition of aninhibitor to the assay mixture results in decreased absorbance and isindicative of thrombin inhibition. Human thrombin (Enzyme ResearchLaboratories, Inc., South Bend, Ind.) at a concentration of 0.2 nM in0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% PEG 6000,can be incubated with various substrate concentrations ranging from 0.20to 0.02 mM. After 25 to 30 minutes of incubation, thrombin activity canbe assayed by monitoring the rate of increase in absorbance at 405 nmwhich arises owing to substrate hydrolysis. Inhibition constants werederived from reciprocal plots of the reaction velocity as a function ofsubstrate concentration using the standard method of Lineweaver andBurk.

Compounds tested in the above assay are considered to be active if theyexhibit a K_(i) of ≦10 μM. Preferred compounds of the present inventionhave K_(i)'s of ≦1 μM. More preferred compounds of the present inventionhave K_(i)'s of ≦0.μM. Even more preferred compounds of the presentinvention have K_(i)'s of ≦0.01 μM. Still more preferred compounds ofthe present invention have K_(i)'s of ≦0.001 μM.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. Theseinclude other anti-coagulant or coagulation inhibitory agents,anti-platelet or platelet inhibitory agents, thrombin inhibitors, orthrombolytic or fibrinolytic agents.

The compounds are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is meant anamount of a compound of Formula I that, when administered alone or incombination with an additional therapeutic agent to a mammal, iseffective to prevent or ameliorate the thromboembolic disease conditionor the progression of the disease.

By “administered in combination” or “combination therapy” it is meantthat the compound of Formula I and one or more additional therapeuticagents are administered concurrently to the mammal being treated. Whenadministered in combination each component may be administered at thesame time or sequentially in any order at different points in time.Thus, each component may be administered separately but sufficientlyclosely in time so as to provide the desired therapeutic effect. Otheranticoagulant agents (or coagulation inhibitory agents) that may be usedin combination with the compounds of this invention include warfarin andheparin, as well as other factor Xa inhibitors such as those describedin the publications identified above under Background of the Invention.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, denotes agents that inhibit platelet function such as byinhibiting the aggregation, adhesion or granular secretion of platelets.Such agents include, but are not limited to, the various knownnon-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin,ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam,diclofenac, sulfinpyrazone, and piroxicam, including pharmaceuticallyacceptable salts or prodrugs thereof. Of the NSAIDS, aspirin(acetylsalicyclic acid or ASA), and piroxicam are preferred. Othersuitable anti-platelet agents include ticlopidine, includingpharmaceutically acceptable salts or prodrugs thereof. Ticlopidine isalso a preferred compound since it is known to be gentle on thegastro-intestinal tract in use. Still other suitable platelet inhibitoryagents include IIb/IIIa antagonists, thromboxane-A2-receptor antagonistsand thromboxane-A2-synthetase inhibitors, as well as pharmaceuticallyacceptable salts or prodrugs thereof.

The term thrombin inhibitors (or anti-thrombin agents), as used herein,denotes inhibitors of the serine protease thrombin. By inhibitingthrombin, various thrombin-mediated processes, such as thrombin-mediatedplatelet activation (that is, for example, the aggregation of platelets,and/or the granular secretion of plasminogen activator inhibitor-1and/or serotonin) and/or fibrin formation are disrupted. A number ofthrombin inhibitors are known to one of skill in the art and theseinhibitors are contemplated to be used in combination with the presentcompounds. Such inhibitors include, but are not limited to, boroargininederivatives, boropeptides, heparins, hirudin and argatroban, includingpharmaceutically acceptable salts and prodrugs thereof. Boroargininederivatives and boropeptides include N-acetyl and peptide derivatives ofboronic acid, such as C-terminal a-aminoboronic acid derivatives oflysine, ornithine, arginine, homoarginine and correspondingisothiouronium analogs thereof. The term hirudin, as used herein,includes suitable derivatives or analogs of hirudin, referred to hereinas hirulogs, such as disulfatohirudin. Boropeptide thrombin inhibitorsinclude compounds described in Kettner et al., U.S. Pat. No. 5,187,157and EP 293 881 A2, the disclosures of which are hereby incorporatedherein by reference. Other suitable boroarginine derivatives andboropeptide thrombin inhibitors include those disclosed in WO92/07869and EP 471,651 A2, the disclosures of which are hereby incorporatedherein by reference.

The term thrombolytics (or fibrinolytic) agents (or thrombolytics orfibrinolytics), as used herein, denotes agents that lyse blood clots(thrombi). Such agents include tissue plasminogen activator,anistreplase, urokinase or streptokinase, including pharmaceuticallyacceptable salts or prodrugs thereof. The term anistreplase, as usedherein, refers to anisoylated plasminogen streptokinase activatorcomplex, as described, for example, in European Patent Application No.028,489, the disclosure of which is hereby incorporated herein byreference herein. The term urokinase, as used herein, is intended todenote both dual and single chain urokinase, the latter also beingreferred to herein as prourokinase.

Administration of the compounds of Formula I of the invention incombination with such additional therapeutic agent, may afford anefficacy advantage over the compounds and agents alone, and may do sowhile permitting the use of lower doses of each. A lower dosageminimizes the potential of side effects, thereby providing an increasedmargin of safety.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the inhibition of factor Xa. Such compoundsmay be provided in a commercial kit, for example, for use inpharmaceutical research involving factor Xa. For example, a compound ofthe present invention could be used as a reference in an assay tocompare its known activity to a compound with an unknown activity. Thiswould ensure the experimenter that the assay was being performedproperly and provide a basis for comparison, especially if the testcompound was a derivative of the reference compound. When developing newassays or protocols, compounds according to the present invention couldbe used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving factor Xa. For example, the presence of factor Xa in anunknown sample could be determined by addition of chromogenic substrateS2222 to a series of solutions containing test sample and optionally oneof the compounds of the present invention. If production of pNA isobserved in the solutions containing test sample, but not in thepresence of a compound of the present invention, then one would concludefactor Xa was present.

Dosage and Formulation

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient,and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will rangefrom about 1 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Representative useful pharmaceutical dosage-forms for administration ofthe compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 100 milligrams of active ingredient, 0.2 milligrams of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams ofmicrocrystalline cellulose, 11 milligrams of starch and 98.8 milligramsof lactose. Appropriate coatings may be applied to increase palatabilityor delay absorption.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.5% by weight of active ingredient in 10t byvolume propylene glycol and water. The solution should be made isotonicwith sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin.

Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 to100 milligrams of the compound of Formula I and about 1 to 7.5milligrams of the second anticoagulant, per kilogram of patient bodyweight. For a tablet dosage form, the compounds of this inventiongenerally may be present in an amount of about 5 to 10 milligrams perdosage unit, and the second anti-coagulant in an amount of about 1 to 5milligrams per dosage unit.

Where the compounds of Formula I are administered in combination with ananti-platelet agent, by way of general guidance, typically a dailydosage may be about 0.01 to 25 milligrams of the compound of Formula Iand about 50 to 150 milligrams of the anti-platelet agent, preferablyabout 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3milligrams of antiplatelet agents, per kilogram of patient body weight.

Where the compounds of Formula I are administered in combination withthrombolytic agent, typically a daily dosage may be about 0.1 to 1milligrams of the compound of Formula I, per kilogram of patient bodyweight and, in the case of the thrombolytic agents, the usual dosage ofthe thrombolytic agent when administered alone may be reduced by about70-80% when administered with a compound of Formula I.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, generally the amount ofeach component in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of Formula I and a second therapeuticagent are combined in a single dosage unit they are formulated such thatalthough the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized (thatis, reduced). For example, one active ingredient may be enteric coated.By enteric coating one of the active ingredients, it is possible notonly to minimize the contact between the combined active ingredients,but also, it is possible to control the release of one of thesecomponents in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial which effects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low-viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise that as specifically describedherein.

What is claimed is:
 1. A compound selected from the group:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;G is selected from the group:

L_(n) is a linker which is absent or is selected from CH₂, *CH₂NHC(O),*CH(R^(a))NHC(O), *CH₂NHC(O)CH₂, and *CH(R^(a))NHC(O)CH₂, and the *indicates where L_(n) is bonded to G; R^(a) is selected fromC(O)C(O)OR³, C(O)C(O)NR²R^(2a), and C(O)—A; R is selected from H, Cl, F,Br, I, (CH₂)_(t)OR³, C₁₋₄ alkyl, benzyl, OCF₃, CF₃, C(O)NR⁷R⁸, and(CR⁸R⁹)_(t)NR⁷R⁸; Z is selected from a (CR⁸R⁹)₁₋₄,(CR⁸R⁹)_(r)O(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)NR³(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)C(O)(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)C(O)O(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)OC(O)(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)C(O)NR³(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)NR³C(O)(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)OC(O)O(CR⁸R⁹)_(r),(CH₂)_(r)OC(O)NR³(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)NR³C(O)O(CR⁸R⁹)_(r),(CH₂)_(r)NR³C(O)NR³(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)S(O)_(p)(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)S(O)₂(CH═CH), (CCR⁸R⁹)_(r)SO₂NR³(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)NR³SO₂(CR⁸R⁹)_(r), and (CR⁸R⁹)_(r)NR³SO₂NR³(CR⁸R⁹)_(r),provided that Z does not form a N—N, N—O, N—S, NCH₂N, NCH₂O, or NCH₂Sbond with the groups to which Z is attached; R^(1′) is selected from H,C₁₋₃ alkyl, F, Cl, Br, I, —CN, —CHO, (CF₂)_(r)CF₃, (CH₂)_(r)OR²,NR²R^(2a), C(O)R^(2c), OC(O)R², (CF₂)_(r)CO₂R^(2c),S(O)_(p)(CH₂)_(r)R^(2b), NR²(CH₂)_(r)OR², C(═NR^(2c))NR²R^(2a),NR²C(O)R^(2b), NR²C(O)NHR^(2b), NR²C(O)₂R^(2a), OC(O)NR^(2a)R^(2b),C(O)NR²R^(2a), C(O)NR²(CH₂)_(r)OR², SO₂NR²R^(2a), NR²SO₂R^(2b), C₃₋₆carbocyclic residue substituted with 0-2 R⁴, and 5-10 memberedheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S substituted with 0-2 R⁴, provided thatif R^(1′) is substituted with R⁴ then R⁴ is other than N(CH₂)₂(CH₂)_(t)R_(1′), O(CH₂)₂(CH₂)_(t)R^(1′), andS(CH₂)₂(CH₂)_(t)R^(1′); R^(1″) is selected from H, CH(CH₂OR²)₂,C(O)R^(2c), C(O)NR²R^(2a), S(O)R^(2b), S(O)₂R^(2b), and SO₂NR²R^(2a);R², at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl,C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 memberedheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S substituted with 0-2 R^(4b); R^(2a), ateach occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆cycloalkylmethyl substituted with 0-2 R^(4b), C₃₋₆ carbocyclic residuesubstituted with 0-2 R^(4b), and 5-6 membered heterocyclic systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-2 R^(4b); R^(2b), at each occurrence, isselected from CF₃, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclicresidue substituted with 0-2 R^(4b), and 5-6 membered heterocyclicsystem containing from 1-4 heteroatoms selected from the groupconsisting of N, O, and S substituted with 0-2 R^(4b); R^(2c), at eachoccurrence, is selected from CF₃, OH, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl,C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 memberedheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S substituted with 0-2 R^(4b);alternatively, R² and R^(2a), together with the atom to which they areattached, combine to form a 5 or 6 membered saturated, partiallysaturated or unsaturated ring substituted with 0-2 R^(4b) and containingfrom 0-1 additional heteroatoms selected from the group consisting of N,O, and S; R³, at each occurrence, is selected from H, C₁₋₄ alkyl, andphenyl; R^(3a), at each occurrence, is selected from H, C₁₋₄ alkyl, andphenyl; R^(3c), at each occurrence, is selected from C₁₋₄ alkyl, andphenyl; A is selected from: C₃₋₁₀ carbocyclic residue substituted with0-2 R⁴, and 5-10 membered heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-2 R⁴; B is selected from: H, Y, and X—Y X is selectedfrom C₁₋₄ alkylene, —CR²(CR²R^(2b))(CH₂)_(t)—, —C(O)—, —CR²(NR^(1″)R²)—,—CR²(OR²)—, —CR²(SR²)—, —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —OS(O)₂—,—S(O)_(p)—, —S(O)_(p)CR²R^(2a)—, —CR²R^(2a)S(O)_(p)—, —S(O)₂NR²—,—NR²S(O)₂—, —NR²S(O)₂CR²R^(2a)—, —CR²R^(2a)S(O)₂NR²—, —NR²S(O)₂NR²—,—C(O)NR²—, —NR²C(O)—, —C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—,—CR²R^(2a)C(O)NR²—, —CR²R^(2a)NR²C(O)—, —NR²C(O)O—, —OC(O)NR²—,—NR²C(O)NR²—, —NR²—, —NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, —CR²R^(2a)O—,and —OCR²R^(2a); Y is selected from: (CH₂)_(r)NR²R^(2a), provided thatX—Y do not form a N—N, O—N, or S—N bond, C₃₋₁₀ carbocyclic residuesubstituted with 0-2 R^(4a), and 5-10 membered heterocyclic systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-2 R^(4a); R⁴, at each occurrence, isselected from H, ═O, (CH₂)_(r)OR², F, Cl, Br, I, C₁₋₄ alkyl, —CN, NO₂,(CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b), C(O)NR²R^(2a),NR²C(O)NR²R^(2a), C(═NR²)NR²R^(2a), C(═NS(O)₂R⁵)NR²R^(2a),NHC(═NR²)NR²R^(2a), C(O)NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a),NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, (CF₂)_(r)CF₃,NHCH₂R^(1″), OCH₂R^(1″), SCH₂R^(1″), N(CH₂)₂(CH₂)_(t)R^(1′),O(CH₂)₂(CH₂)_(t)R^(1′), and S(CH₂)₂(CH₂)_(t)R^(1′); alternatively, oneR⁴ is a 5-6 membered aromatic heterocycle containing from 1-4heteroatoms selected from the group consisting of N, O, and S; R^(4a),at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², (CH₂)_(r)—F,(CH₂)_(r)—Br, (CH₂)_(r)—Cl, Cl, Br, F, I, C₁₋₄ alkyl, —CN, NO₂,(CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b), C(O)NR²R^(2a),C(O)NH(CH₂)₂NR²R^(2a), NR²C(O)NR²R^(2a), C(═NR²)R^(3c),C(═NR²)NR²R^(2a), NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a),NR²SO₂—C₁₋₄ alkyl, C(O)NHSO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, and(CF₂)_(r)CF₃; alternatively, one R^(4a) is a 5-6 membered aromaticheterocycle containing from 1-4 heteroatoms selected from the groupconsisting of N, O, and S substituted with 0-1 R⁵; R^(4b), at eachoccurrence, is selected from H, ═O, (CH₂)_(r)OR³, F, Cl, Br, I, C₁₋₄alkyl, —CN, NO₂, (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³,(CH₂)_(r)C(O)OR^(3c), NR³C(O)R^(3a), C(O)NR³R^(3a), NR³C(O) NR³R^(3a),C(═NR³)NR³R^(3a), NR³C(═NR³)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂NR³R^(3a),NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃, NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄alkyl, S(O)_(p)-phenyl, and (CF₂)_(r)CF₃; R⁵, at each occurrence, isselected from CF₃, C₁₋₆ alkyl, phenyl substituted with 0-2 R⁶, andbenzyl substituted with 0-2 R⁶; R⁶, at each occurrence, is selected fromH, OH, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r)NR²R^(2a),(CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), NR²C(O)NR²R^(2a), C(═NH)NH₂,NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂NR²R^(2a), and NR²SO₂C₁₋₄ alkyl; R⁷, ateach occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl,C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, (CH₂)_(n)-phenyl, C₆₋₁₀ aryloxy, C₆₋₁₀aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl;R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and(CH₂)_(n)-phenyl; alternatively, R⁷ and R⁸ combine to form a 5 or 6membered saturated, ring which contains from 0-1 additional heteroatomsselected from the group consisting of N, O, and S; R⁹, at eachoccurrence, is selected from H, C₁₋₆ alkyl and (CH₂)_(n)-phenyl; n, ateach occurrence, is selected from 0, 1, 2, and 3; p, at each occurrence,is selected from 0, 1, and 2; r, at each occurrence, is selected from 0,1, 2, and 3; and, t, at each occurrence, is selected from 0, 1, 2, and3.
 2. A compound selected from the group:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;G is selected from the group:

L_(n) is a linker which is absent or is selected from O, S, CH₂,*CH₂NHC(O), *CH(R^(a))NHC(O), *CH₂NHC(O)CH₂, and *CH(R^(a))NHC(O)CH₂,provided that L_(n) and M do not form an O—N or S—N bond and the *indicates where L_(n) is bonded to G; R^(a) is selected fromC(O)C(O)OR³, C(O)C(O)NR²R^(2a), and C(O)—A; R is selected from H, Cl, F,Br, I, (CH₂)_(t)OR³, C₁₋₄ alkyl, benzyl, OCF₃, CF₃, C(O)NR⁷R⁸, and(CR⁸R⁹)_(t)NR⁷R⁸; Z is selected from a (CR⁸R⁹)₁₋₄,(CR⁸R⁹)_(r)O(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)NR³(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)C(O)(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)C(O)O(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)OC(O)(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)C(O)NR³(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)NR³C(O)(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)OC(O)O(CR⁸R⁹)_(r),(CH₂)_(r)OC(O)NR³(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)NR³C(O)O(CR⁸R⁹)_(r),(CH₂)_(r)NR³C(O)NR³(CR⁸R⁹)_(r), (CR⁸R⁹)_(r)S(O)_(p)(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)S(O)₂(CH═CH), (CCR⁸R⁹)_(r)SO₂NR³(CR⁸R⁹)_(r),(CR⁸R⁹)_(r)NR³SO₂(CR⁸R⁹)_(r), and (CR⁸R⁹)_(r)NR³SO₂NR³(CR⁸R⁹)_(r),provided that Z does not form a N—N, N—O, N—S, NCH₂N, NCH₂O, or NCH₂Sbond with the groups to which Z is attached; R^(1′) is selected from H,C₁₋₃ alkyl, F, Cl, Br, I, —CN, —CHO, (CF2)_(r)CF₃, (CH₂)_(r)OR²,NR²R^(2a), C(O)R^(2c), OC(O)R², (CF₂)_(r)CO₂R^(2c),S(O)_(p)(CH₂)_(r)R^(2b), NR²(CH₂)_(r)OR², C(═NR^(2c))NR²R^(2a),NR²C(O)R^(2b), NR²C(O)NHR^(2b), NR²C(O)₂R^(2a), OC(O)NR^(2a)R^(2b),C(O)NR²R^(2a), C(O)NR²(CH₂)_(r)OR², SO₂NR²R^(2a), NR²SO₂R^(2b), C₃₋₆carbocyclic residue substituted with 0-2 R⁴, and 5-10 memberedheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S substituted with 0-2 R⁴, provided thatif R^(1′) is substituted with R⁴ then R⁴ is other thanN(CH₂)₂(CH₂)_(t)R^(1′), O(CH₂)₂(CH₂)_(t)R^(1′), andS(CH₂)₂(CH₂)_(t)R^(1′); R^(1″) is selected from H, CH(CH₂OR²)₂,C(O)R^(2c), C(O)NR²R^(2a), S(O)R^(2b), S(O)₂R^(2b), and SO₂NR²R^(2a);R², at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl,C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 memberedheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S substituted with 0-2 R^(4b); R^(2a), ateach occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆cycloalkylmethyl substituted with 0-2 R^(4b), C₃₋₆ carbocyclic residuesubstituted with 0-2 R^(4b), and 5-6 membered heterocyclic systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-2 R^(4b); R^(2b), at each occurrence, isselected from CF₃, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclicresidue substituted with 0-2 R^(4b), and 5-6 membered heterocyclicsystem containing from 1-4 heteroatoms selected from the groupconsisting of N, O, and S substituted with 0-2 R^(4b); R^(2c), at eachoccurrence, is selected from CF₃, OH, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl,C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 memberedheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S substituted with 0-2 R^(4b);alternatively, R² and R^(2a), together with the atom to which they areattached, combine to form a 5 or 6 membered saturated, partiallysaturated or unsaturated ring substituted with 0-2 R^(4b) and containingfrom 0-1 additional heteroatoms selected from the group consisting of N,O, and S; R³, at each occurrence, is selected from H, C₁₋₄ alkyl, andphenyl; R^(3a), at each occurrence, is selected from H, C₁₋₄ alkyl, andphenyl; R^(3c), at each occurrence, is selected from C₁₋₄ alkyl, andphenyl; A is selected from: C₃₋₁₀ carbocyclic residue substituted with0-2 R⁴, and 5-10 membered heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-2 R⁴; B is selected from: H, Y, and X—Y X is selectedfrom C₁₋₄ alkylene, —CR²(CR²R^(2b))(CH₂)_(t)—, —C(O)—, —CR²(NR^(1″)R²)—,—CR²(OR²)—, —CR²(SR²)—, —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —OS(O)₂—,—S(O)_(p)—, —S(O)_(p)CR²R^(2a)—, —CR²R^(2a)S(O)_(p)—, —S(O)₂NR²—,—NR²S(O)₂—, —NR²S(O)₂CR²R^(2a)—, —CR²R^(2a)S(O)₂NR²—, —NR²S(O)₂NR²—,—C(O)NR²—, —NR²C(O)—, —C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—,—CR²R^(2a)C(O)NR²—, —CR²R^(2a)NR²C(O)—, —NR²C(O)O—, —OC(O)NR²—,—NR²C(O)NR²—, —NR²—, —NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, —CR²R^(2a)O—,and —OCR²R^(2a)—; Y is selected from: (CH₂)_(r)NR²R^(2a), provided thatX—Y do not form a N—N, O—N, or S—N bond, C₃₋₁₀ carbocyclic residuesubstituted with 0-2 R^(4a), and 5-10 membered heterocyclic systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-2 R^(4a); R⁴, at each occurrence, isselected from H, ═O, (CH₂)_(r)OR², F, Cl, Br, I, C₁₋₄ alkyl, —CN, NO₂,(CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b), C(O)NR²R^(2a),NR²C(O)NR²R^(2a), C(═NR²)NR²R^(2a), C(═NS(O)₂R⁵)NR²R^(2a),NHC(═NR²)NR²R^(2a), C(O)NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a),NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, (CF₂)_(r)CF₃,NHCH₂R^(1″), OCH₂R^(1″), SCH₂R^(1″), N(CH₂)₂(CH₂)_(t)R^(1′),O(CH₂)₂(CH₂)_(t)R^(1′), and S(CH₂)₂(CH₂)_(t)R^(1′); alternatively, oneR⁴ is a 5-6 membered aromatic heterocycle containing from 1-4heteroatoms selected from the group consisting of N, O, and S; R⁴a, ateach occurrence, is selected from H, ═O, (CH₂)_(r)OR², (CH₂)_(r)—F,(CH₂)_(r)—Br, (CH₂)_(r)—Cl, Cl, Br, F, I, C₁₋₄ alkyl, —CN, NO₂,(CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b), C(O)NR²R^(2a),C(O)NH(CH₂)₂NR²R^(2a), NR²C(O)NR²R^(2a), C(═NR²)R^(3c),C(═NR²)NR²R^(2a), NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a),NR²SO₂—C₁₋₄ alkyl, C(O)NHSO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, and(CF₂)_(r)CF₃; alternatively, one R^(4a) is a 5-6 membered aromaticheterocycle containing from 1-4 heteroatoms selected from the groupconsisting of N, O, and S substituted with 0-1 R⁵; R^(4b), at eachoccurrence, is selected from H, ═O, (CH₂)_(r)OR³, F, Cl, Br, I, C₁₋₄alkyl, —CN, NO₂, (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³,(CH₂)_(r)C(O)OR^(3c), NR³C(O)R^(3a), C(O)NR³R^(3a), NR³C(O)NR³R^(3a),C(═NR³) NR³R^(3a), NR³C(═NR³)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂NR³R^(3a),NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃, NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄alkyl, S(O)_(p)-phenyl, and (CF₂)_(r)CF₃; R⁵, at each occurrence, isselected from CF₃, C₁₋₆ alkyl, phenyl substituted with 0-2 R⁶, andbenzyl substituted with 0-2 R⁶; R⁶, at each occurrence, is selected fromH, OH, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, CN, NO₂,(CH₂)_(r)NR²R^(2a),(CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), NR²C(O)NR²R^(2a),C(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂NR²R^(2a), and NR²SO₂C₁₋₄alkyl; R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, (CH₂)_(n)-phenyl, C₆₋₁₀aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenylC₁₋₄ alkoxycarbonyl; R⁸, at each occurrence, is selected from H, C₁₋₆alkyl and (CH₂)_(n)-phenyl; alternatively, R⁷ and R⁸ combine to form a 5or 6 membered saturated, ring which contains from 0-1 additionalheteroatoms selected from the group consisting of N, O, and S; R⁹, ateach occurrence, is selected from H, C₁₋₆ alkyl and (CH₂)_(n)-phenyl; n,at each occurrence, is selected from 0, 1, 2, and 3; p, at eachoccurrence, is selected from 0, 1, and 2; r, at each occurrence, isselected from 0, 1, 2, and 3; and, t, at each occurrence, is selectedfrom 0, 1, 2, and
 3. 3. A compound according to claim 2, wherein: G isselected from the group:

R is selected from H, Cl, F, Br, I, (CH₂)_(t)OR³, C₁₋₄ alkyl, OCF₃, CF₃,C(O)NR⁷R⁸, and (CR⁸R⁹)_(t)NR⁷R⁸; Z is selected from a CH₂O, OCH₂, CH₂NH,NHCH₂, C(O), CH₂C(O), C(O)CH₂, NHC(O), C(O)NH, CH₂S(O)₂, S(O)₂(CH₂),SO₂NH, and NHSO₂, provided that Z does not form a N—N, N—O, NCH₂N, orNCH₂O bond with ring M or group A; A is selected from one of thefollowing carbocyclic and heterocyclic systems which are substitutedwith 0-2 R⁴; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl,furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl,benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, andisoindazolyl; B is selected from: H, Y, and X—Y; X is selected from C₁₋₄alkylene, —C(O)—, —C(═NR)—, —CR²(NR²R^(2a))—, —C(O)CR²R^(2a)—,—CR²R^(2a)C(O), —C(O)NR²—, —NR²C(O)—, —C(O)NR²CR²R^(2a)—,—NR²C(O)CR²R^(2a)—, —CR²R^(2a)C(O)NR²—, —CR²R^(2a)NR²C(O) —,—NR²C(O)NR²—, —NR²—, —NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, —CR²R^(2a)O—,and —OCR²R^(2a)—; Y is NR²R^(2a) or CH₂NR²R^(2a), provided that X—Y donot form a N—N or O—N bond; alternatively, Y is selected from one of thefollowing carbocyclic and heterocyclic systems which are substitutedwith 0-2 R^(4a); cyclopropyl, cyclopentyl, cyclohexyl, phenyl,piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl,thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl,thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl,benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, andisoindazolyl; alternatively, Y is selected from the following bicyclicheteroaryl ring systems:

K is selected from O, S, NH, and N.
 4. A compound according to claim 3,wherein: G is selected from:

Z is C(O)CH₂ and CONH, provided that Z does not form a N—N bond withgroup A; A is selected from phenyl, pyridyl, and pyrimidyl, and issubstituted with 0-2 R⁴; and, B is selected from Y, X—Y, phenyl,pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and issubstituted with 0-1 R^(4a); X is selected from CH₂, —C(O)—, and O; Y isNR²R^(2a) or CH₂NR²R^(2a), provided that X—Y does not form an O—N bond;alternatively, Y is selected from one of the following carbocyclic andheterocyclic systems which are substituted with 0-2 R^(4a); phenyl,piperazinyl, pyridyl, pyrimidyl, morpholinyl, pyrrolidinyl, imidazolyl,and 1,2,3-triazolyl; R², at each occurrence, is selected from H, CF₃,CH₃, benzyl, and phenyl; R^(2a), at each occurrence, is selected from H,CF₃, CH₃, CH(CH₃)₂, cyclopropylmethyl, benzyl, and phenyl;alternatively, R² and R^(2a) combine to form a ring system substitutedwith 0-2 R^(4b), the ring system being selected from pyrrolidinyl,piperazinyl and morpholino; R⁴, at each occurrence, is selected from OH,(CH₂)_(r)OR², Cl, F, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), and (CF₂)_(r)CF₃;R^(4a) is selected from Cl, F, C₁₋₄ alkyl, CF₃, (CH₂)_(r)NR²R^(2a),S(O)_(p)R⁵, SO₂NR²R^(2a), and 1-CF₃-tetrazol-2-yl; R^(4b), at eachoccurrence, is selected from OH, Cl, F, CH₃, and CF₃; R⁵, at eachoccurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, and benzyl; R⁷, ateach occurrence, is selected from H, CH₃, and CH₂CH₃; and, R⁸, at eachoccurrence, is selected from H and CH₃.
 5. A compound according to claim4, wherein: A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl,2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl,2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and, B is selectedfrom the group: 2-CF₃-phenyl, 2-(aminosulfonyl)phenyl,2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl,1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl,2-(N,N-dimethylaminomethyl)phenyl, 2-(isopropylaminomethyl)phenyl,2-(cyclopropylaminomethyl)phenyl, 2-(N-pyrrolidinylmethyl)phenyl,2-(3-hydroxy-N-pyrrolidinylmethyl)phenyl, 4-morpholino,2-(1′-CF₃-tetrazol-2-yl)phenyl, 4-morpholinocarbonyl,1-methyl-2-imidazolyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl,2-(N,N-dimethylaminomethyl)imidazolyl, 2-methylsulfonyl-1-imidazolyland, 5-methyl-1,2,3-triazolyl.
 6. A compound according to claim 3,wherein: G is selected from the group:

R is selected from H, C₁, F, Br, I, (CH₂)_(t)OR³, C₁₋₄ alkyl, OCF₃, CF₃,C(O)NR⁷R⁸, and (CR⁸R⁹)_(t)NR⁷R⁸; Z is selected from a CH₂O, OCH₂, CH₂NH,NHCH₂, C(O), CH₂C(O), C(O)CH₂, NHC(O), C(O)NH, CH₂S(O)₂, S(O)₂(CH₂),SO₂NH, and NHSO₂, provided that Z does not form a N—N, N—O, NCH₂N, orNCH₂O bond with ring M or group A; A is selected from one of thefollowing carbocyclic and heterocyclic systems which are substitutedwith 0-2 R⁴; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl,furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl,benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, andisoindazolyl; B is selected from: H, Y, and X—Y; X is selected from C₁₋₄alkylene, —C(O)—, —C(═NR)—, —CR²(NR²R^(2a))—, —C(O)CR²R^(2a)—,—CR²R^(2a)C(O), —C(O)NR²—, —NR²C(O)—, —C(O)NR²CR²R^(2a)—,—NR²C(O)CR²R^(2a)—, —CR²R^(2a)C(O)NR²—, —CR²R^(2a)NR²C(O)—,—NR²C(O)NR²—, —NR²—, —NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, —CR²R^(2a)O—,and —OCR²R^(2a)—; Y is NR²R^(2a) or CH₂NR²R^(2a), provided that X—Y donot form a N—N or O—N bond; alternatively, Y is selected from one of thefollowing carbocyclic and heterocyclic systems which are substitutedwith 0-2 R^(4a); cyclopropyl, cyclopentyl, cyclohexyl, phenyl,piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl,thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl,thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl,benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, andisoindazolyl; alternatively, Y is selected from the following bicyclicheteroaryl ring systems:

K is selected from O, S, NH, and N.
 7. A compound according to claim 6,wherein: G is selected from:

Z is C(O)CH₂ and CONH, provided that Z does not form a N—N bond withgroup A; A is selected from phenyl, pyridyl, and pyrimidyl, and issubstituted with 0-2 R⁴; and, B is selected from Y, X—Y, phenyl,pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and issubstituted with 0-1 R^(4a); X is selected from CH₂, —C(O)—, and O; Y isNR²R^(2a) or CH₂NR²R^(2a), provided that X—Y does not form an O—N bond;alternatively, Y is selected from one of the following carbocyclic andheterocyclic systems which are substituted with 0-2 R^(4a); phenyl,piperazinyl, pyridyl, pyrimidyl, morpholinyl, pyrrolidinyl, imidazolyl,and 1,2,3-triazolyl; R², at each occurrence, is selected from H, CF₃,CH₃, benzyl, and phenyl; R^(2a), at each occurrence, is selected from H,CF₃, CH₃, CH(CH₃)₂, cyclopropylmethyl, benzyl, and phenyl;alternatively, R² and R^(2a) combine to form a ring system substitutedwith 0-2 R^(4b), the ring system being selected from pyrrolidinyl,piperazinyl and morpholino; R⁴, at each occurrence, is selected from OH,(CH₂)_(r)OR², Cl, F, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), and (CF2)_(r)CF₃;R^(4a) is selected from Cl, F, C₁₋₄ alkyl, CF₃, (CH₂)_(r)NR²R^(2a),S(O)_(p)R⁵, SO₂NR²R^(2a), and 1-CF₃-tetrazol-2-yl; R_(4b), at eachoccurrence, is selected from OH, Cl, F, CH₃, and CF₃; R⁵, at eachoccurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, and benzyl; R⁷, ateach occurrence, is selected from H, CH₃, and CH₂CH₃; and, R⁸, at eachoccurrence, is selected from H and CH₃.
 8. A compound according to claim7, wherein: A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl,2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl,2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and, B is selectedfrom the group: 2-CF₃-phenyl, 2-(aminosulfonyl)phenyl,2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl,1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl,2-(N,N-dimethylaminomethyl)phenyl, 2-(isopropylaminomethyl)phenyl,2-(cyclopropylaminomethyl)phenyl, 2-(N-pyrrolidinylmethyl)phenyl,2-(3-hydroxy-N-pyrrolidinylmethyl)phenyl, 4-morpholino,2-(1′-CF₃-tetrazol-2-yl)phenyl, 4-morpholinocarbonyl,1-methyl-2-imidazolyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl,2-(N,N-dimethylaminomethyl)imidazolyl, 2-methylsulfonyl-1-imidazolyland, 5-methyl-1,2,3-triazolyl.
 9. A compound of the formula:

L_(n) is *CH₂NHC(O)CH₂or *CH(R^(a))NHC(O)CH₂ and the * indicates whereL_(n) is bonded to G; G is selected from the group;

R^(a) is C(O)C(O)OR³; R, at each occurrence, is selected from H, Cl, F,Br, I, OR³, C₁₋₄ alkyl, C(O)NH₂, and NH₂; Z is (CHR⁸)NR³, (CHR⁸)₂NR³, orSO₂R³(CHR⁸)₂; provided that when Z is SO₂R³(CHR⁸)₂, then B is absent;R², at each occurrence, is selected from H, C₁₋₆ alkyl, benzyl, andphenyl; R^(2a), at each occurrence, is selected from H, C₁₋₆ alkyl,benzyl, and phenyl; R^(2c), at each occurrence, is selected from OH,OCH₃, OCH₂CH₃, CH₃, benzyl, and phenyl; R³, at each occurrence, isselected from H, C₁₋₄ alkyl, and phenyl; R^(3a), at each occurrence, isselected from H, C₁₋₄ alkyl, and phenyl; B is H or Y; Y is selectedfrom; C₅₋₆ carbocyclic residue substituted with 0-2 R^(4a), and 5-6membered heterocyclic system containing from 1-2 heteroatoms selectedfrom the group consisting of N, O, and S substituted with 0-2 R^(4a);R^(4a), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², Cl,Br, F, I, C₁₋₄ alkyl, —CN, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),C(O)NR²R^(2a), SO₂NR^(2a), and CF₃; R⁸, at each occurrence, is selectedfrom H, C₁₋₆ alkyl and phenyl; and r, at each occurrence, is selectedfrom 0, 1, 2, and
 3. 10. A compound according to claim 9, wherein: L_(n)is *CH₂NHC(O)CH₂ and the * indicates where L_(n) is bonded to G; R, ateach occurrence, is selected from H and C₁₋₄ alkyl; Z is (CHR⁸)NR³,(CHR⁸)₂NR³, or SO₂R³(CHR⁸)₂; provided that when Z is SO₂R³(CHR⁸)₂, thenB is absent; B is H or Y; Y is phenyl substituted with 0-1 R⁴, pyridylsubstituted with 0-1 R⁴ or N-morpholino substituted with 0-1 R⁴; R⁴, ateach occurrence, is selected from H, and C₁₋₄ alkyl; R⁸, at eachoccurrence, is selected from H, methyl and phenyl; and, r, at eachoccurrence, is selected from 0, 1, and
 2. 11. A compound according toclaim 10, wherein: G is selected from:


12. A pharmaceutical composition, comprising: a pharmaceuticallyacceptable carrier and a therapeutically effective amount of a compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof. 13.A pharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 2 or a pharmaceutically acceptable salt thereof.
 14. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 9 or a pharmaceutically acceptable salt thereof.
 15. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 10 or a pharmaceutically acceptable salt thereof.
 16. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 6 or a pharmaceutically acceptable salt thereof.
 17. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 7 or a pharmaceutically acceptable salt thereof.
 18. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 8 or a pharmaceutically acceptable salt thereof.
 19. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 11 or a pharmaceutically acceptable salt thereof.
 20. A methodfor treating a thromboembolic disorder, comprising: administering to apatient in need thereof a therapeutically effective amount of a compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof. 21.A method for treating a thromboembolic disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a compound according to claim 2 or a pharmaceuticallyacceptable salt thereof.
 22. A method for treating a thromboembolicdisorder, comprising: administering to a patient in need thereof atherapeutically effective amount of a compound according to claim 9 or apharmaceutically acceptable salt thereof.
 23. A method for treating athromboembolic disorder, comprising: administering to a patient in needthereof a therapeutically effective amount of a compound according toclaim 10 or a pharmaceutically acceptable salt thereof.
 24. A method fortreating a thromboembolic disorder, comprising: administering to apatient in need thereof a therapeutically effective amount of a compoundaccording to claim 6 or a pharmaceutically acceptable salt thereof. 25.A method for treating a thromboembolic disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a compound according to claim 7 or a pharmaceuticallyacceptable salt thereof.
 26. A method for treating a thromboembolicdisorder, comprising: administering to a patient in need thereof atherapeutically effective amount of a compound according to claim 8 or apharmaceutically acceptable salt thereof.
 27. A method for treating athromboembolic disorder, comprising: administering to a patient in needthereof a therapeutically effective amount of a compound according toclaim 11 or a pharmaceutically acceptable salt thereof.